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From Hao Wu, Sarah G. Hymowitz, Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface. In: Ralph A. Bradshaw and Edward A. Dennis, editors, Handbook of Cell Signaling 2nd edition.

Oxford: Academic Press, 2009, pp. 265-275. ISBN: 978-0-12-374145-5

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265Handbook of Cell Signaling, Three-Volume Set 2 ed.Copyright © 2009 Elsevier Inc. All rights reserved.2010

Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface

Hao Wu1 and Sarah G. Hymowitz2

1Department of Biochemistry, Weill Cornell Medical College, New York, New York2Department of Structural Biology, Genentech Inc., South San Francisco, California

IntroductIon

The tumor necrosis factor (TNF) superfamily (TNFSF) and the TNF receptor (TNFR) superfamily (TNFRSF) form the corresponding ligand and receptor systems that are widely distributed in different tissues and cell types. Collectively they play critical roles in numerous aspects of mamma-lian biology, including embryonic development, innate and adaptive immunity, and maintenance of cellular homeos-tasis [1–3]. Agents that manipulate the signaling of these receptors are being used or showing promise towards the treatment and prevention of many human diseases [4–6].

Historically, the phrase tumor necrosis factor referred to a “factor” induced by bacterial infections that caused tumor regression in anecdotal cases. As early as the late nineteenth century, attempts were made to treat many kinds of cancers by provoking acute local skin infections, sometimes with success [7]. In 1975, it was discovered that bacterial endotoxin induced the production and release of anti-tumor activity from host cells. This activity caused hemorrhagic necrosis of transplanted tumors in mice, and killed transformed cell lines [8]. Its promise as a cancer cure prompted many laboratories to search the molecular identity of TNF. This eventually led to the purification, characterization, and cloning of TNF, and the realization that the wasting-inducing factor cachexia is identical to TNF [9–12].

It was soon discovered that TNF has a wide range of biological effects in host defense against pathogens. On a cellular level, it is capable of inducing cell survival, prolif-eration, and differentiation, as well as both apoptotic and necrotic cell death under certain conditions [13, 14]. These collections of effects are mediated by the two receptors of TNF, TNF-R1 and TNF-R2 [15]. TNF does not gener-ally provoke cell killing as in its anti-tumor activity, but

more often promotes gene transcription and cell activation. There are currently 18 TNFSF members and 28 TNFRSF members that comprise signaling receptors, decoy recep-tors, and orphan receptors (Figure 40.1, Table 40.1). Some ligands and receptors interact with more than one partner, increasing the regulatory flexibility and complexity. Over 30 years of research since the cloning of TNF has led to the thriving field of TNFSF and TNFRSF, with an esti-mated number of publications of over 100,000 and a TNF congress that meets every 2 years.

Structural featureS

TNFSF members are generally homotrimeric type II trans-membrane proteins, many of which can be shed from the cell surface to act as soluble signaling molecules. The defining feature of this family of extracellular ligands is the trimeric TNF homology domain (THD), comprising of three jelly roll protomers (Figure 40.2a, Table 40.2). Each protomer is formed by two -sheets composed of strands AAHCF and BBGDE. These domains are exclusively located at the C-terminal region of the protein. The fam-ily can be divided into three groups (the conventional, the EF-disulfide containing, and the divergent), based on sequence and structural features in the THD. The “con-ventional” TNFSF members include TNF, LT, LT, LT2, Apo2L/TRAIL, TL1A, LIGHT, FasL, RANKL and CD40L. This group is well characterized functionally and structurally, with crystal structures available for most of the ligands [16]. These ligands all have relatively long loops connecting the CD, DF, and DE strands, resulting in a char-acteristic pyramidal shape of the trimer. All “conventional” ligands are expected to bind receptors in a similar manner, with the elongated receptors nestled in the ligand–protomer

Chapter 40

Author’s personal copy

Part | I Initiation: Extracellular and Membrane Events266

interfaces with two significant contact areas. One of the contact areas includes interactions between the receptor and conserved hydrophobic features in the ligand DE loop.

The second TNFSF subfamily, the “EF-disulfide” group, consists of APRIL, BAFF, TWEAK, and EDA, all of which possess a characteristic disulfide connecting the E and F strands. In addition, these ligands have shorter CD and EF loops, which lead to a more globular THD in contrast to the pyramidal conventional ligands. Crystal structures are avail-able for APRIL, BAFF, and EDA ([17–21]). Receptor bind-ing by this TNFSF group also differs from the conventional ligands, as they lack the conserved hydrophobic residues in the DE loop. Three of these ligands (APRIL, BAFF, and TWEAK) interact with small, atypical TNFRSF members (BAFF-R, TACI, BCMA, and Fn14) [16].

The third “divergent” ligand group contains the remaining members of the TNFSF (CD27L, CD30L, GITRL, 4-1BBL, and OX40L). These ligands are characterized by very diver-gent sequences, both from each other and from either the conventional or EF-disulfide groups. This group, despite the greater sequence divergence, is the least well studied crystal-lographically. Crystal structures have only been determined for the ligands OX40L and GITRL [22–24], and for the receptor–ligand pair OX40–OX40L [23]. These structures have shown evidence of greater plasticity in both the ligands

and ligand–receptor complexes than had previously been appreciated. For instance, the trimer interface in both OX40L and GITRL is considerably smaller than in other ligands, leading the ligands to have an “open” appearance. Based on biophysical characterization of GITRL, the dissociation con-stant for trimer assembly appears to be lower than for other members of the TNFSF, with more extensive trimeric inter-faces. Most surprisingly, two independent crystal structures of the extracellular domain of recombinant mouse GITRL, but not human GITRL, indicate a dimer both in the crystal and in solution [25] [24,26]. The functional consequences of this alternative dimeric packing in mouse GITRL are still being explored.

The corresponding TNFRSF members are type I trans-membrane proteins that share certain structural features in their extracellular domains [3]. In contrast to the globu-lar ligands, the typical multidomain TNFRSF members are elongated molecules composed of an extracellular domain of multiple 40-residue pseudo repeats, typically contain-ing six cysteines forming three disulfides (Figure 40.2b). These modules are termed CRDs (cysteine-rich domains), and can be further subdivided into smaller submodules based on the number of cysteines and topology of the cysteine con-nectivity [27]. A typical CRD is composed of A1 and B2 tandemly linked subdomains. The A1 subdomain contains a

TNFαLTαLTβLIGHT

FasLTL1ARANKL

TRAIL

TWEAK

CD40LOX40LGITRLCD30LCD27L4-1BBLEDA-A1EDA-A2

APRILBAFF

NGFR(NGF)

THD CRD DD

BAFF-RBCMATACITROYXEDAREDAR4-1BBCD27CD30GITROX40CD40DR6Fn14DcR2DcR1DR5DR4OPGRANKDR3FasDcR3HVEM

TNF-R2TNF-R1

LTβR

fIgure 40.1 Ligand : receptor interaction map between the TNFSF and the TNFRSF.THD, TNF homology domain; CRD, cysteine-rich domain; DD, death domain.


chapter | 40 Structure and Function of Tumor Necrosis Factor (TNF) at the Cell Surface 267

Table 40.1 The TNFSF and TNFRSF

Standardized names Common names Standardized names Common names

TNFSF1 LT, TNF, LT TNFRSF1A TNF-R1, CD120a, p55-R, TNFR60

TNFSF2 TNF, TNF, cachectin TNFRSF1B TNF-R2, CD120b, p75-R, TNFR80

TNFSF3 LT TNFRSF3 LTR

TNFSF4 OX40L TNFRSF4 OX40, CD134

TNFSF5 CD40L, CD154 TNFRSF5 CD40

TNFSF6 FasL, CD95 TNFRSF6 Fas, CD95, Apo-1

TNFRSF6B DcR3

TNFSF7 CD27L, CD70 TNFRSF7 CD27

TNFSF8 CD30L TNFRSF8 CD30

TNFSF9 4-1BBL TNFRSF9 4-1BB, CD137

TNFSF10 TRAIL, Apo-2L, TL2 TNFRSF10A DR4, Apo-2, TRAIL-R1

TNFRSF10B DR5, TRAIL-R2

TNFRSF10C DcR1, TRAIL-R3

TNFRSF10D DcR2, TRAIL-R4

TNFSF11 RANKL, TRANCE, OPGL TNFRSF11A RANK, TRANCE-R,

TNFRSF11B OPG, osteoprotegerin

TNFSF12 TWEAK, Apo-3L TNFRSF12A Fn14, TWEAK-R

TNFSF13 APRIL TNFRSF13B TACI, CAML interactor

TNFSF13B BAFF, Blys, TALL1 TNFRSF13C BAFF-R, BR3

TNFRSF17 BCMA, BCM

TNFSF14 LIGHT, HVEM-L, LT TNFRSF14 HVEM, HveA, ATAR, LIGHT-R

TNFSF15 TL1A, VEGI TNFRSF12 DR3, Apo-3, TRAMP

TNFSF18 GITRL, AITRL, TL6 TNFRSF18 GITR, AITR

Eda, Ectodysplasin EDAR

XEDAR, EDA-A2R

(NGF) TNFRSF16 NGFR, p75

TNFRSF19 TROY, TAJ, TRADD

TNFRSF21 DR6



single disulfide (the 1–2 disulfide), while the B2 subdomain contains two disulfides that are linked in a 3–5, 4–6 topol-ogy. Other subdomain variants exist, such as the A2 that contains two disulfides or the B1 that lacks one of the char-acteristic disulfides. This fold is preserved in viral proteins, such as CrmE, that modulate host immune systems [28].

Though less common, there are some TNFRSF mem-bers (BCMA, Fn14, BAFF-R) that only contain a single or partial CRD [16]. The BAFF and APRIL receptor TACI

also belongs to this group of the TNFRSF, despite the apparent appearance of two CRDs in the TACI sequence. Biophysical, structural, and sequence analysis suggests that the two CRDs of TACI are likely the consequence of a rel-atively recent duplication event, and that only the second CRD is functional [29].

Despite the variety of ligand and receptor diversity within the family, to date all of the TNFSF : TNFRSF complexes oligomerize by binding receptor at each of the

(a)

(b) (c) (d)fIgure 40.2 Structures of TNFSF and TNFRSF members and complexes.(a) Three subtypes of TNFSF members. Ligands are oriented such that the ligand termini are on the top. Left, C trace of LT trimer showing the pyramidal shape of the “conventional” family members (pdb code, 1TNR). Middle, C trace of the EDA-A2 trimer showing the globular shape of the “EF-disulfide” family members (pdb code, 1RJ8). Right, C trace of the OX40L trimer showing the open packing of the “divergent” family members (pdb code, 2HEV). (b) C trace of the TNF-R1 extracellular domain (pdb code, 1EXT). The sulfur atoms of the characteristic disulfide linkages are shown as spheres. The receptor is oriented such that the receptor cell membrane would be at the bottom of the page. CRDs are labeled. (c) A typical ligand : receptor complex illustrating that the receptor binds in the protomer interfaces (pdb code, 1TNR). LT is shown as a molecular surface and the TNF-R1 extracellular domain is shown as dark gray C ribbon. (d) An “EF-disulfide” ligand : single-CRD receptor complex illustrating that the receptor binds in the protomer interfaces (pdb code, 1XU1). APRIL is shown as a molecular surface and the TACI extracellular domain is shown as dark gray C ribbon. Top, axis view highlighting the three-receptor : one-ligand trimer assembly; Bottom, side view highlighting the receptor binding sites in the ligand protomer–protomer interfaces.



Table 40.2 Crystal structures of extracellular domains of TNF family ligands and receptors

Names Years PDB codes References

Ligands

TNF 1989, 1997, 1998 1TNF, 2TUN, 2TNF, 5TSW, 4TSV, 1A8M 99–102

TNF: compound 2005 2AZ5 91

CD40L 1995 1ALY 103

CD40L : Fab 2001 1I9R 104

TRAIL 1999, 2000 1D2Q, 1DG6 105, 106

RANKL 2001, 2002 1JTZ, 1IQA 107, 108

BAFF 2002 1KD7, 1JH5, 1KXG 18–20

APRIL 2004 1U5X, 1U5Y, 1U5Z 21

EDA-A1 2003 1RJ8 17

EDA-A2 2003 1RJ7 17

OX40L 2006 2HEW 23

TL1A 2007 2O0O, 2RE9, 2QE3 109

hGITL 2007, 2008 3B93, 3B94, 2R32, 2R30, 2Q1M 25, 110

mGITL 2008 3B9I, 2QDN, 2Q8O 24, 26

Receptors

TNF-R1 1995, 1996 1NCF, 1EXT 111, 112

TNF-R1 : compound 2001 1FT4 89

DR5 : Fab 2005, 2006 1ZA3, 2H9G 113, 114

HVEM : gD 2001 1JMA 115

HVEM : BTLA 2005 2AW2 116

CrmE 2007 2UWI 28

NGFR : NGF 2004 1SG1 117

NGFR : NT3 2008 3BUK 118

Ligand : receptor complexes

LT:TNF-R1 1993 1TNR 30

TRAIL : DR5 1999, 2000 1D0G1, 1D4V, 1DU3 31–33

BAFF : BAFF-R 2003 1OQE 35

BAFF : BCMA 2003 1OQD 35

April : BCMA 2005 1XU2 29

April : TACI 2005 1XU1 29

OX40L : OX40 2006 2HEY, 2HEV 23

H, human; m, mouse. The structures of human and mouse GITL are trimers and domain-swapped dimers, respectivelyFab, antibody Fab fragment; gD, Herpes simplex virus envelope glycoprotein D; BTLA, B and T lymphocyte attenuator, a CD28-like protein; CrmE, a Vaccinia virus-encoded tumour necrosis factor receptor; NGF, nerve growth factor; NT3, neurotrophin-3.



ligand–protomer interfaces to create a 3 : 3 heterotrimer (Figure 40.2c). For the multi-domain receptors, struc-tures of LT : TNF-R1 [30], TRAIL : DR5 [31–33], and OX40 : OX40L [23] revealed that the ligand : receptor bind-ing surface is formed primarily by residues from CRD2 and 3, but that additional contacts from CRD1 are also pos-sible. The small single-domain receptors such as BCMA or BAFF-R also bind the ligand–protomer interfaces, but the interaction is focused at the end of the protomer interface away from the ligand termini [29,34,35] (Figure 40.2d). In either case, complex formation results in clustering of recep-tor extracellular domains in a signaling-competent manner. In the BAFF : BCMA and BAFF : BAFF-R complexes, the extracellular domain of BAFF forms a virus-like assembly that further cluster the receptors into higher order [35].

SIgnalIng PathwayS and regulatIon

Unlike many receptors, TNFRSF members do not possess enzymatic activity. Instead, the oligomeric complexes pre-sumably place the intracellular regions of the receptors into proximity for recruitment of signaling proteins with enzy-matic activities to amplify the signal transduction. Prior to ligand binding, at least some TNFRSF members, such as Fas, TNF-R1, TNF-R2, DR4, and CD40, appear to exist in pre-formed non-signaling oligomers through a region of the extracellular domain named the pre-ligand-binding assem-bly domain (PLAD) [36, 37]. The PLAD is likely physic-ally separate from the ligand binding site and appears to be required for many aspects of receptor signaling, including dominant interference by receptors with pathogenic muta-tions at the PLAD region [37].

The signaling pathways of TNFRSF members differ depending on the domain and sequence in the intracellular region. Some of the receptors do not contain a structural module known as the death domain (DD) in their intracel-lular domains and are “survival” receptors, which directly recruit adaptor proteins known as the TNF receptor asso-ciated factors (TRAFs) [38–40]. Some examples of “sur-vival” receptors include TNF-R2, CD40, CD30, OX40, 4-1BB, LTR, RANK, and TACI. Seven mammalian TRAFs (TRAF1–7) have been identified so far, some of which are ubiquitin ligases [41, 42]. Among these, TRAF1, 2, 3, 5, and 6 participate in the signal transduction of the TNFRSF, lead-ing to activation of transcription factors in the nuclear factor -B (NF-B) and activator protein-1 (AP-1) family [43, 44].

Some TNFRSF members, such as Fas and TNF-R1, con-tain an intracellular DD and are known as death receptors [4, 45]. Fas is an effective prototypical cell-killing receptor. The intracellular DD of Fas directly recruits a DD-containing protein known as Fas-associated DD (FADD) via DD–DD interactions [46]. FADD also contains a death-effector domain (DED), which further recruits the DED-containing

pro-caspase-8 or pro-caspase-10 to elicit caspase activation and apoptosis [47–49]. DR4 and DR5 also recruit FADD and caspase-8 or caspase-10, similar to Fas [50]. TNF-R1-like death receptors, on the other hand, possess the intrinsic capability of both cell-death and cell-survival induction. The underlying mechanism for this duality lies on the recruit-ment of a multifunctional protein, TNF receptor-associated DD (TRADD), via DD : DD domain interactions, by TNF-R1 [51]. TRADD recruits TRAF2 [51–53] and FADD [51, 54], leading to both survival and death signaling in a “cel-lular context”-dependent manner.

Many structures of TRAF proteins in complex with receptor sequences and adaptor proteins have been deter-mined, which showed a matching trimeric symmetry of TRAFs and specificity of recognition [42, 55]. For a more detailed review of these structures, please refer to Chapter 49 of this book. Many DD and DED structures are known, including those involved in TNFRSF signaling. However, no structures of DD : DD or DED : DED complexes in the TNFRSF pathways are currently available [56]. A recent oligomeric structure of a DD : DD complex involved in caspase activation following DNA damage showed a com-pletely asymmetric assembly mechanism that may provide a template for understanding these interactions [57].

Receptor signaling may be regulated by various means, such as by naturally occurring decoy receptors including OPG and DcR3 and by receptor shedding from the cell surface [58]. The latter may be a mechanism for terminat-ing inflammation in a temporally controlled manner, and genetic defect in the shedding of TNF-R1 is a major cause of periodic fever syndromes [59].

BIologIcal functIonS

Biological functions of the TNFSF and TNFRSF reflect their signaling capabilities, such as activation of transcription fac-tors NFB and AP-1 for cell survival and differentiation, and activation of caspases for cell-death induction. Although some TNFRSF members share similar intracellular signaling pathways, they can exert specific, non-redundant biological functions. First, many receptors exhibit specific tissue distri-bution patterns, and are induced by different developmental cues or environmental stimuli. Second, the intracellular sign-aling pathways of these receptors are differentially regulated, resulting in diverse cellular effects.

TNFSF and TNFRSF are major coordinators in the devel-opment of many organs, such as lymphoid organs, mammary glands and hair follicles. Secondary lymphoid organs are located at strategic sites where foreign antigens can be effi-ciently brought together with immune system regulatory and effector cells. The organized structure of secondary lymphoid tissues is thought to enhance sensitivity of antigen recogni-tion, and to support proper regulation of activation of anti-gen-responsive lymphoid cells. LT, LTR, RANKL, and



RANK are indispensable for the development of such lym-phoid organs, including the spleen and lymph nodes [60–63]. Genetic studies suggest that the requirement for RANKL : RANK and for LT : LTR in lymph-node formation may be sequential. CD4 hematopoietic precursor cells emigrating into the primordial lymph node first use RANKL : RANK for survival and differentiation [63]. The ensuing expression of LT then allows interaction of these precursor cells with stromal connective tissue cells that express LTR to establish spatial constraints in lymphoid organ definition, and to com-plete maturation of the node [60].

The RANKL : RANK system is important for termi-nal differentiation of mammary gland for lactation during pregnancy [64]. It is interesting that RANKL : RANK is also important for bone homeostasis (see below); coordi-nated activation of osteoclasts and maturation of mammary gland may be important for mobilization of minerals from the mother’s bone to the newborn. The TNFRSF members EDAR, XEDAR, and TROY play roles in hair-follicle and sweat-gland development. Mice deficient in either EDA or EDAR, or humans with mutations in these proteins, have no primary hair follicles or sweat glands [65, 66]. In con-trast, another TNFRSF member, p75, appears to temporally coordinate hair follicle development [67]. Interestingly, p75 is a receptor for the dimeric NGF, which is not part of the TNFSF. It plays multiple roles in neuronal development, including sensory neuron development, and p75-deficient mice exhibit decreased sensory innervation and serious cutaneous sensorineural defects [68, 69].

The TNFSF and TNFRSF are major coordinators in innate immune response and acute inflammation. Pathogen-associated molecular patterns such as lipopolysaccharides (LPS), peptidoglycan, flagellin, bacterial DNA CpG motifs, and viral RNAs activate cell surface and intracellular recep-tors, such as the Toll-like receptors (TLRs) and Nod-like receptors [70–72]. Cytokines such as TNF are secreted upon pathogen recognition, which in turn lead to produc-tion and upregulation of chemokines and adhesion mol-ecules. This is mostly mediated by the ability of TNF to activate transcription factors in the NFB family, which tar-get the expression of proteins in immune and inflammatory responses. Chemokines and adhesion molecules are crucial for rapid recruitment of inflammatory cells such as granulo-cytes, monocytes, and lymphocytes to the site of infection. Massive reaction to pathogens can lead to septic shock, and TNF or TNFR deficiency attenuates these events [73].

TNFSF and TNFRSF also participate in acute adaptive immune response, primarily through their effect on forma-tion of B-cell rich germinal centers (GCs) within second-ary lymphoid organs during an antigen response. TNFSF and TNFRSF members such as TNF, LT, LT, TNF-R1, and LTR coordinate the formation of networks of follicular dendritic cells (FDC) that provide the environment of GCs [60]. FDCs are specialized mesenchymal cells that collect antigens in draining lymph nodes and interact with clonally

expanding B cells in GCs. The engagement of the TNFRSF member CD40 on the B cells by CD40L on T cells is crucial for B cell somatic hypermutation and subsequent selection of high-affinity B cells for Ig class switching [74, 75]. Another TNFSF member, BAFF, on dendritic cells, interacts with its receptors on B cells to enhance B cell survival, which can augment autoimmunity under pathological conditions [3, 75]. TNFRSF members such as OX40, 4-1BB, CD27, CD30, HVEM, and GITR promote the expansion and sur-vival of CD4 and CD8 T cells upon stimulation by den-dritic cells that bear the corresponding ligands [76, 77].

The TNFRSF comprises various death receptors (DRs). One major function of certain DRs is to mediate the kill-ing of virus-infected cells by CD8 cytotoxic T cells. This effect has been well known for Fas [78]. Another function of DR-mediated death is immune homeostasis to balance recur-rent lymphocyte expansion in response to antigen. This is crucial because of the limited space of lymphoid organs and toxic effects of massive lymphocyte expansion [79]. High or repeated antigen stimulation of activated T cells may induce these death molecules, and causes apoptosis in a fraction of the expanding cell population. Genetic impairment of Fas-induced apoptosis in humans or mice causes a dramatic loss of lymphocyte homeostasis and autoimmunity. While some DRs can induce caspase activation and apoptosis, some DRs, such as TNF-R1, can also mediate death of viral-infected cells that more resembles necrosis [80].

In addition to their role in lymphocyte homeostasis, the TNFSF and TNFRSF members such as RANK, RANKL, and TNF play important roles in bone homeostasis. RANK and RANKL are important for differentiation and activation of osteoclasts from a monocyte precursor, and their absence leads to overly dense bones [62]. TNF both synergizes with RANKL [81] and acts independently to induce osteoclast development in RANK deficient mice [82]. Bone homeostasis is not autonomous, but integrated with immune and hormonal functions. Activated T cells promote bone loss because RANKL expression is induced by antigen receptor engagement, which contributes to joint inflammation, bone and cartilage destruction, and crip-pling in arthritis [83]. The soluble RANKL decoy receptor OPG is induced by estrogen [84], and estrogen deficiency induces bone loss by enhancing T cell production of TNF [85]. Therefore, the decrease in estrogen levels after meno-pause may explain the prevalence of osteoporosis.

theraPeutIcS and future exPectatIonS

Due to their role in a variety of important biological pro-cesses, including inflammation and apoptosis, many TNFSF and TNFRSF members have been targeted with therapeutic agents. Three anti-TNF agents targeting TNF to suppress its inflammatory activities have been approved, including



the TNF-R2–Fc fusion Enteracept (EnbrelTM), and two antibody-based agents, Infliximab (RemicadeTM) and Adalimumab (HumiraTM). These drugs have been used for treatment against autoimmune diseases such as rheumatoid arthritis, psoriasis, Crohn’s disease, and ulcerative colitis. Recent biochemical characterizations have shown that the epitopes of Enbrel and Infliximab are energetically distinct, although they can compete for TNF under some circum-stances [86]. Recombinant TNF has been approved for isolated limb perfusion therapy in melanoma [87].

TRAIL receptors DR4 and DR5 are highly expressed on many kinds of cancer cells, and recombinant human TRAIL and agonistic DR4 and DR5 antibodies are being investigated in clinical trials for their uses in cancer treat-ment [88]. On the other hand, inhibiting Fas with the use of the soluble Fas-Fc decoy receptor is being considered for inhibiting apoptosis in spinal cord injury [87]. Due to the relatively large interfaces, targeting the extracellular por-tion of these receptors and ligands with small molecules as agonists or antagonists is a challenging task. However, a variety of approaches have been tried, with some suc-cess [89–93]. There is also the possibility of inhibiting the intracellular signal transduction of TNFRSF members. One example is the use of cell-permeable TRAF6 binding pep-tides in downregulating RANK signaling and osteoclast differentiation in primary monocytes [94].

Interestingly, although recombinant TNF has only been approved for limited use in melanoma, a strik-ing recent finding showed that TNF is a major agent of tumor-cell killing by Smac mimetics [95]. Smac is a pro-tein that normally resides in the inter-membrane space of mitochondria and is released to cytosol during apoptosis to antagonize inhibition of apoptosis proteins (IAPs). A recent finding is that Smac mimetics activate the ubiquitin ligase activity of cIAP1 and cIAP2, leading to activation of NF-B and induction of TNF secretion [96–98]. The low level of TNF in turn causes tumor-cell death in the pres-ence of these mimetics. There are great expectations of the TNFSF and TNFRSF for their wider uses in future thera-pies against cancer and immune diseases.

acknowledgement

This work was funded by the National Institute of Health (AI45937, AI50872, and AI76927). We apologize to all whose work has not been appropriately reviewed or cited due to space limitations.

referenceS

1. Smith CA, Farrah T, Goodwin RG. The TNF receptor superfamily of cellular and viral proteins: activation, costimulation and death. Cell 1994;76:959–62.

2. Gravestein LA, Borst J. Tumor necrosis factor receptor family mem-bers in the immune system. Sem Immunol 1998;10:423–34.

3. Locksley RM, Killeen N, Lenardo MJ. The TNF and TNF recep-tor superfamilies: integrating mammalian biology. Cell 2001;104: 487–501.

4. Ashkenazi A, Dixit VM. Death receptors: signaling and modulation. Science 1998;281:1305–8.

5. Leonen WAM. Editorial overview: CD27 and (TNFR) relatives in the immune system: their role in health and disease. Sem Immunol 1998;10:417–22.

6. Newton RC, Decicco CP. Therapeutic potential and strategies for inhibiting tumor necrosis factor-a. J Med Chem 1999;42:2295–314.

7. Coley WB. The treatment of malignant tumors by repeated inocula-tions of erysipelas: with a report of ten original cases. Am J Med Sci 1893;105:487–511.

8. Carswell EA, Old LJ, Kassel RL, Green S, Fiore N, Williamson B. An endotoxin-induced serum factor that causes necrosis of tumors. Proc Natl Acad Sci USA 1975;72:3666–70.

9. Pennica D, Nedwin GE, Hayflick JS, Seeburg PH, Derynck R, Palladino MA, Kohr WJ, Aggarwal BB, Goeddel DV. Human tumour necrosis factor: precursor structure, expression and homology to lym-photoxin. Nature 1984;312:724–9.

10. Wang AM, Creasey AA, Ladner MB, Lin LS, Strickler J, Van Arsdell JN, Yamamoto R, Mark DF. Molecular cloning of the complementary DNA for human tumor necrosis factor. Science 1985;228:149–54.

11. Shirai T, Yamaguchi H, Ito H, Todd CW, Wallace RB. Cloning and expression in Escherichia coli of the gene for human tumour necrosis factor. Nature 1985;313:803–6.

12. Beutler B, Cerami A. Cachectin and tumour necrosis factor as two sides of the same biological coin. Nature 1986;320:584–8.

13. Goeddel DV, Aggarwal BB, Gray PW, Leung DW, Nedwin GE, Palladino MA, Patton JS, Pennica D, Shepard HM, Sugarman BJ, et al. Tumor necrosis factors: gene structure and biological activities. Cold Spring Harb Symp Quant Biol 1986;51(Pt 1):597–609.

14. Fiers W. Tumor necrosis factor. Characterization at the molecular, cel-lular and in vivo level. FEBS Letts 1991;285:199–212.

15. Lewis M, Tartaglia LA, Lee A, Bennett GL, Rice GC, Wong GH, Chen EY, Goeddel DV. Cloning and expression of cDNAs for two dis-tinct murine tumor necrosis factor receptors demonstrate one receptor is species specific. Proc Natl Acad Sci USA 1991;88:2830–4.

16. Bodmer JL, Schneider P, Tschopp J. The molecular architecture of the TNF superfamily. Trends Biochem Sci 2002;27:19–26.

17. Hymowitz SG, Compaan DM, Yan M, Wallweber HJ, Dixit VM, Starovasnik MA, de Vos AM. The crystal structures of EDA-A1 and EDA-A2: splice variants with distinct receptor specificity. Structure 2003;11:1513–20.

18. Karpusas M, Cachero TG, Qian F, Boriack-Sjodin A, Mullen C, Strauch K, Hsu YM, Kalled SL. Crystal structure of extracellular human BAFF, a TNF family member that stimulates B lymphocytes. J Mol Biol 2002;315:1145–54.

19. Liu Y, Xu L, Opalka N, Kappler J, Shu HB, Zhang G, et al. Crystal structure of sTALL-1 reveals a virus-like assembly of TNF family lig-ands. Cell 2002;108:383–94.

20. Oren DA, Li Y, Volovik Y, Morris TS, Dharia C, Das K, Galperina O, Gentz R, Arnold E. Structural basis of BLyS receptor recognition. Nature Struct Biol 2002;9:288–92.

21. Wallweber HJ, Compaan DM, Starovasnik MA, Hymowitz SG. The crystal structure of a proliferation-inducing ligand, APRIL. J Mol Biol 2004;343:283–90.



22. Chattopadhyay K, et al. Structural basis of inducible costimulator ligand costimulatory function: determination of the cell surface oligo-meric state and functional mapping of the receptor binding site of the protein. J Immunol 2006;177:3920–9.

23. Compaan DM, Hymowitz SG. The crystal structure of the costimula-tory OX40–OX40L complex. Structure 2006;14:1321–30.

24. Zhou Z, Tone Y, Song X, Furuuchi K, Lear JD, Waldmann H, Tone M, Greene MI, Murali R. Structural basis for ligand-mediated mouse GITR activation. Proc Natl Acad Sci USA 2008;105:641–5.

25. Chattopadhyay K, Ramagopal UA, Mukhopadhaya A, Malashkevich VN, Dilorenzo TP, Brenowitz M, Nathenson SG, Almo SC. Assembly and structural properties of glucocorticoid-induced TNF receptor ligand: implications for function. Proc Natl Acad Sci USA 2007;104:19,452–7.

26. Chattopadhyay K, Ramagopal UA, Brenowitz M, Nathenson SG, Almo SC. Evolution of GITRL immune function: murine GITRL exhibits unique structural and biochemical properties within the TNF superfamily. Proc Natl Acad Sci USA 2008;105:635–40.

27. Naismith JH, Sprang SR. Modularity in the TNF-receptor family. Trends Biochem Sci 1998;23:74–9.

28. Graham SC, Bahar MW, Abrescia NG, Smith GL, Stuart DI, Grimes JM. Structure of CrmE, a virus-encoded tumour necrosis factor recep-tor. J Mol Biol 2007;372:660–71.

29. Hymowitz SG, Patel DR, Wallweber HJ, Runyon S, Yan M, Yin J, Shriver SK, Gordon NC, Pan B, Skelton NJ, Kelley RF, Starovasnik MA. Structures of APRIL-receptor complexes: like BCMA, TACI employs only a single cysteine-rich domain for high affinity ligand binding. J Biol Chem 2005;280:7218–27.

30. Banner DW, D’Arcy A, Janes W, Gentz R, Schoenfeld JJ, Broger C, Loetscher H, Lesslauer W. Crystal structure of the soluble human 55-kD TNF receptor–human TNF- complex: implications for TNF receptor activation. Cell 1993;73:431–45.

31. Cha SS, Sung BJ, Kim YA, Song YL, Kim HJ, Kim S, Lee MS, Oh BH. Crystal structure of TRAIL–DR5 complex identifies a critical role of the unique frame insertion in conferring recognition specifi-city. J Biol Chem 2000;275:31,171–7.

32. Hymowitz SG, Christinger HW, Fuh G, Ultsch M, O’Connell M, Kelley RF, Ashkenazi A, de Vos AM. Triggering cell death: the crystal structure of Apo2L/TRAIL in a complex with death receptor 5. Mol Cell 1999;4:563–71.

33. Mongkolsapaya J, Grimes JM, Chen N, Xu XN, Stuart DI, Jones EY, Screaton GR. Structure of the TRAIL–DR5 complex reveals mecha-nisms conferring specificity in apoptotic initiation. Nature Struct Biol 1999;6:1048–53.

34. Kim HM, Yu KS, Lee ME, Shin DR, Kim YS, Paik SG, Yoo OJ, Lee H, Lee JO. Crystal structure of the BAFF–BAFF-R complex and its implications for receptor activation. Nature Struct Biol 2003;10:342–8.

35. Liu Y, Hong X, Kappler J, Jiang L, Zhang R, Xu L, Pan CH, Martin WE, Murphy RC, Shu HB, Dai S, Zhang G. Ligand–receptor binding revealed by the TNF family member TALL-1. Nature 2003;423:49–56.

36. Chan FK, Chun HJ, Zheng L, Siegel RM, Bui KL, Lenardo MJ. A domain in TNF receptors that mediates ligand-independent receptor assembly and signaling. Science 2000;288:2351–4.

37. Siegel RM, Frederiksen JK, Zacharias DA, Chan FK, Johnson M, Lynch D, Tsien RY, Lenardo MJ. Fas preassociation required for apoptosis signaling and dominant inhibition by pathogenic mutations. Science 2000;288:2354–7.

38. Rothe M, Wong SC, Henzel WJ, Goeddel DV. A novel family of puta-tive signal transducers associated with the cytoplasmic domain of the 75-kDa tumor necrosis factor receptor. Cell 1994;78:681–92.

39. Arch RH, Gedrich RW, Thompson CB. Tumor necrosis factor receptor- associated factors (TRAFs) – a family of adapter proteins that regu-lates life and death. Genes Dev 1998;12:2821–30.

40. Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated sig-nal transduction. J Cell Sci 2002;115:679–88.

41. Wu H. Assembly of post-receptor signaling complexes for the tumor necrosis factor receptor superfamily. Adv Protein Chem 2004;68:225–79.

42. Chung JY, Lu M, Yin Q, Wu H. Structural revelations of TRAF2 function in TNF receptor signaling pathway. Adv Exp Med Biol 2007;597:93–113.

43. Ghosh S, Karin M. Missing pieces in the NF-B puzzle. Cell 2002;109(Suppl.):S81–96.

44. Shaulian E, Karin M. AP-1 as a regulator of cell life and death. Nature Cell Biol 2002;4:E131–6.

45. Nagata S. Apoptosis by death factor. Cell 1997;88:355–65. 46. Chinnaiyan AM, O’Rourke K, Tewari M, Dixit VM. FADD, a novel

death domain-containing protein, interacts with the death domain of Fas and initiates apoptosis. Cell 1995;81:505–12.

47. Boldin MP, Goncharov TM, Goltsev YV, Wallach D. Involvement of MACH, a novel MORT1/FADD-interacting protease, in Fas/APO-1- and TNF receptor-induced cell death. Cell 1996;85:803–15.

48. Muzio M, Chinnaiyan AM, Kischkel FC, O’Rourke K, Shevchenko A, Ni J, Scaffidi C, Bretz JD, Zhang M, Gentz R, Mann M, Krammer PH, Peter ME, Dixit VM. FLICE, a novel FADD-homologous ICE/CED-3-like protease, is recruited to the CD95 (Fas/APO-1) death-inducing signaling complex. Cell 1996;85:817–27.

49. Wang J, Chun HJ, Wong W, Spencer DM, Lenardo MJ. Caspase-10 is an initiator caspase in death receptor signaling. Proc Natl Acad Sci USA 2001;98:13,884–8.

50. LeBlanc HN, Ashkenazi A. Apo2L/TRAIL and its death and decoy receptors. Cell Death Diff 2003;10:66–75.

51. Hsu H, Shu H-B, Pan M-G, Goeddel DV. TRADD–TRAF2 and TRADD–FADD interactions define two distinct TNF receptor 1 sig-nal transduction pathways. Cell 1996;84:299–308.

52. Yeh WC, Shahinian A, Speiser D, Kraunus J, Billia F, Wakeham A, de la Pompa JL, Ferrick D, Hum B, Iscove N, Ohashi P, Rothe M, Goeddel DV, Mak TW. Early lethality, functional NF-B activation, and increased sensitivity to TNF-induced cell death in TRAF2- deficient mice. Immunity 1997;7:715–25.

53. Kelliher MA, Grimm S, Ishida Y, Kuo F, Stanger BZ, Leder P. The death-domain kinase RIP mediates the TNF-induced NF-kB signal. Immunity 1998;8:297–303.

54. Micheau O, Tschopp J. Induction of TNF receptor I-mediated apopto-sis via two sequential signaling complexes. Cell 2003;114:181–90.

55. Chung JY, Lu M, Yin Q, Lin SC, Wu H. Molecular basis for the unique specificity of TRAF6. Adv Exp Med Biol 2007;597:122–30.

56. Park HH, Lu M, Yin Q, Lin SC, Wu H. The death domain superfamily in intracellular signaling of apoptosis and inflammation. Annu Rev Immunology 2007;25:561–86.

57. Park HH, Logette E, Rauser S, Cuenin S, Walz T, Tschopp J, Wu H. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 2007;128:533–46.

58. Kepler TB, Chan C. Spatiotemporal programming of a simple inflam-matory process. Immunol Rev 2007;216:153–63.



59. Stojanov S, McDermott MF. The tumour necrosis factor receptor-associated periodic syndrome: current concepts. Expert Rev Mol Med 2005;7:1–18.

60. Fu YX, Chaplin DD. Development and maturation of secondary lym-phoid tissues. Annu Rev Immunol 1999;17:399–433.

61. Dougall WC, Logette E, Rauser S, Cuenin S, Walz T, Tschopp J, Wu H. RANK is essential for osteoclast and lymph node development. Genes Dev 1999;13:2412–24.

62. Kong YY, Yoshida H, Sarosi I, Tan HL, Timms E, Capparelli C, Morony S, Oliveira-dos-Santos AJ, Van G, Itie A, Khoo W, Wakeham A, Dunstan CR, Lacey DL, Mak TW, Boyle WJ, Penninger JM. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 1999;397:315–23.

63. Kim D, Mebius RE, MacMicking JD, Jung S, Cupedo T, Castellanos Y, Rho J, Wong BR, Josien R, Kim N, Rennert PD, Choi Y. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J Exp Med 2000;192:1467–78.

64. Fata JE, Kong YY, Li J, Sasaki T, Irie-Sasaki J, Moorehead RA, Elliott R, Scully S, Voura EB, Lacey DL, Boyle WJ, Khokha R, Penninger JM. The osteoclast differentiation factor osteoprotegerin-ligand is essen-tial for mammary gland development. Cell 2000;103:41–50.

65. Headon DJ, Overbeek PA. Involvement of a novel TNF receptor homologue in hair follicle induction. Nature Genet 1999;22:370–4.

66. Monreal AW, Ferguson BM, Headon DJ, Street SL, Overbeek PA, Zonana J. Mutations in the human homologue of mouse dl cause autosomal recessive and dominant hypohidrotic ectodermal dysplasia. Nature Genet 1999;22:366–9.

67. Botchkareva NV, Botchkarev VA, Chen LH, Lindner G, Paus R. A role for p75 neurotrophin receptor in the control of hair follicle morphogenesis. Dev Biol 1999;216:135–53.

68. Lee KF, Li E, Huber LJ, Landis SC, Sharpe AH, Chao MV, Jaenisch R. Targeted mutation of the gene encoding the low affinity NGF receptor p75 leads to deficits in the peripheral sensory nervous system. Cell 1992;69:737–49.

69. Bibel M, Barde YA. Neurotrophins: key regulators of cell fate and cell shape in the vertebrate nervous system. Genes Dev 2000;14:2919–37.

70. Martinon F, Tschopp J. NLRs join TLRs as innate sensors of patho-gens. Trends Immunol 2005;26:447–54.

71. Kawai T, Akira S. TLR signaling. Cell Death Diff 2006;13:816–25. 72. Seth RB, Sun L, Chen ZJ. Antiviral innate immunity pathways. Cell

Res 2006;16:141–7. 73. Yeh WC, Hakem R, Woo M, Mak TW. Gene targeting in the analy-

sis of mammalian apoptosis and TNF receptor superfamily signaling. Immunol Rev 1999;169:283–302.

74. Grewal IS, Flavell RA. CD40 and CD154 in cell-mediated immunity. Annu Rev Immunol 1998;16:111–35.

75. Cozine CL, Wolniak KL, Waldschmidt TJ. The primary germinal center response in mice. Curr Opin Immunol 2005;17:298–302.

76. So T, Lee SW, Croft M. Tumor necrosis factor/tumor necrosis fac-tor receptor family members that positively regulate immunity. Intl J Hematol 2006;83:1–11.

77. Scheu S, Alferink J, Potzel T, Barchet W, Kalinke U, Pfeffer K. Targeted disruption of LIGHT causes defects in costimulatory T cell activation and reveals cooperation with lymphotoxin beta in mesenteric lymph node genesis. J Exp Med 2002;195:1613–24.

78. Nagata S, Golstein P. The Fas death factor. Science 1995;267:1449–56. 79. Brenner D, Krammer PH, Arnold R. Concepts of activated T cell

death. Crit Rev Oncol Hematol 2008;66:52–64. 80. Li M, Beg AA. Induction of necrotic-like cell death by tumor necro-

sis factor alpha and caspase inhibitors: novel mechanism for killing virus-infected cells. J Virol 2000;74:7470–7.

81. Lam J, Takeshita S, Barker JE, Kanagawa O, Ross FP, Teitelbaum SL. TNF- induces osteoclastogenesis by direct stimulation of mac-rophages exposed to permissive levels of RANK ligand. J Clin Invest 2000;106:1481–8.

82. Li J, Sarosi I, Yan XQ, Morony S, Capparelli C, Tan HL, McCabe S, Elliott R, Scully S, Van G, Kaufman S, Juan SC, Sun Y, Tarpley J, Martin L, Christensen K, McCabe J, Kostenuik P, Hsu H, Fletcher F, Dunstan CR, Lacey DL, Boyle WJ. RANK is the intrinsic hematopoi-etic cell surface receptor that controls osteoclastogenesis and regula-tion of bone mass and calcium metabolism. Proc Natl Acad Sci USA 2000;97:1566–71.

83. Wu H, Arron JR. TRAF6, a molecular bridge spanning adaptive immunity, innate immunity and osteoimmunology. Bioessays 2003;25:1096–105.

84. Hofbauer LC, Khosla S, Dunstan CR, Lacey DL, Spelsberg TC, Riggs BL. Estrogen stimulates gene expression and protein produc-tion of osteoprotegerin in human osteoblastic cells. Endocrinology 1999;140:4367–70.

85. Cenci S, Weitzmann MN, Roggia C, Namba N, Novack D, Woodring J, Pacifici R. Estrogen deficiency induces bone loss by enhancing T-cell production of TNF-. J Clin Invest 2000;106:1229–37.

86. Kim MS, Lee SH, Song MY, Yoo TH, Lee BK, Kim YS. Comparative analyses of complex formation and binding sites between human tumor necrosis factor-alpha and its three antagonists elucidate their different neutralizing mechanisms. J Mol Biol 2007;374:1374–88.

87. Fischer U, Schulze-Osthoff K. Apoptosis-based therapies and drug targets. Cell Death Diff 2005;12(Suppl. 1):942–61.

88. Ashkenazi A. Targeting the extrinsic apoptosis pathway in cancer. Cytokine Growth Factor Rev 2008;19:325–31.

89. Carter PH, Scherle PA, Muckelbauer JK, Voss ME, Liu RQ, Thompson LA, Tebben AJ, Solomon KA, Lo YC, Li Z, Strzemienski P, Yang G, Falahatpisheh N, Xu M, Wu Z, Farrow NA, Ramnarayan K, Wang J, Rideout D, Yalamoori V, Domaille P, Underwood DJ, Trzaskos JM, Friedman SM, Newton RC, Decicco CP. Photochemi-cally enhanced binding of small molecules to the tumor necrosis fac-tor receptor-1 inhibits the binding of TNF-. Proc Natl Acad Sci USA 2001;98:11,879–84.

90. Fournel S, Wieckowski S, Sun W, Trouche N, Dumortier H, Bianco A, Chaloin O, Habib M, Peter JC, Schneider P, Vray B, Toes RE, Offringa R, Melief CJ, Hoebeke J, Guichard G. C3-symmetric peptide scaffolds are functional mimetics of trimeric CD40L. Nature Chem Biol 2005;1:377–82.

91. He MM, Smith AS, Oslob JD, Flanagan WM, Braisted AC, Whitty A, Cancilla MT, Wang J, Lugovskoy AA, Yoburn JC, Fung AD, Farrington G, Eldredge JK, Day ES, Cruz LA, Cachero TG, Miller SK, Friedman JE, Choong IC, Cunningham BC. Small-mol-ecule inhibition of TNF-. Science 2005;310:1022–5.

92. Murali R, Smith AS, Oslob JD, Flanagan WM, Braisted AC, Whitty A, Cancilla MT, Wang J, Lugovskoy AA, Yoburn JC, Fung AD, Farrington G, Eldredge JK, Day ES, Cruz LA, Cachero TG, Miller SK, Friedman JE, Choong IC, Cunningham BC. Disabling TNF receptor signaling by induced conformational perturbation of tryptophan–107. Proc Natl Acad Sci USA 2005;102:10,970–5.

93. Trouche N, Wieckowski S, Sun W, Chaloin O, Hoebeke J, Fournel S, Guichard G. Small multivalent architectures mimicking homotrim-ers of the TNF superfamily member CD40L: delineating the rela-tionship between structure and effector function. J Am Chem Soc 2007;129:13,480–92.

94. Ye H, Arron JR, Lamothe B, Cirilli M, Kobayashi T, Shevde NK, Segal D, Dzivenu OK, Vologodskaia M, Yim M, Du K, Singh S, Pike JW, Darnay BG, Choi Y, Wu H. Distinct molecular mechanism for initiating TRAF6 signalling. Nature 2002;418:443–7.



95. Wu H, Tschopp J, Lin SC. Smac mimetics and TNF-: a dangerous liaison? Cell 2007;131:655–8.

96. Petersen SL, Wang L, Yalcin-Chin A, Li L, Peyton M, Minna J, Harran P, Wang X. Autocrine TNF signaling renders human cancer cells susceptible to Smac-mimetic-induced apoptosis. Cancer Cell 2007;12:445–56.

97. Vince JE, Wong WW, Khan N, Feltham R, Chau D, Ahmed AU, Benetatos CA, Chunduru SK, Condon SM, McKinlay M, Brink R, Leverkus M, Tergaonkar V, Schneider P, Callus BA, Koentgen F, Vaux DL, Silke J. IAP antagonists target cIAP1 to induce TNF-dependent apoptosis. Cell 2007;131:682–93.

98. Varfolomeev E, Blankenship JW, Wayson SM, Fedorova AV, Kayagaki N, Garg P, Zobel K, Dynek JN, Elliott LO, Wallwebe HJ. IAP antagonists induce autoubiquitination of c-IAPs, NF-B activa-tion, and TNF-dependent apoptosis. Cell 2007;131:669–81.

99. Jones EY, Stuart DI, Walker NP. Structure of tumour necrosis factor. Nature 1989;338:225–8.

100. Eck MJ, Sprang SR. The structure of tumor necrosis factor-alpha at 2.6 Å resolution. Implications for receptor binding. J Biol Chem 1989;264:17,595–17,605,.

101. Cha SS, Kim JS, Cho HS, Shin NK, Jeong W, Shin HC, Kim YJ, Hahn JH, Oh BH. High resolution crystal structure of a human tumor necrosis factor-alpha mutant with low systemic toxicity. J Biol Chem 1998;273:2153–60.

102. Reed C, Fu ZQ, Wu J, Xue YN, Harrison RW, Chen MJ, Weber IT. Crystal structure of TNF- mutant R31D with greater affinity for receptor R1 compared with R2. Protein Eng 1997;10:1101–7.

103. Karpusas M, Hsu YM, Wang JH, Thompson J, Lederman S, Chess L, Thomas D. 2 A crystal structure of an extracellular fragment of human CD40 ligand. Structure 1995;3:1031–9.

104. Karpusas M, Lucci J, Ferrant J, Benjamin C, Taylor FR, Strauch K, Garber E, Hsu YM. Structure of CD40 ligand in complex with the Fab fragment of a neutralizing humanized antibody. Structure 2001;9:321–9.

105. Cha SS, Kim MS, Choi YH, Sung BJ, Shin NK, Shin HC, Sung YC, Oh BH. 2.8 A resolution crystal structure of human TRAIL, a cytokine with selective antitumor activity. Immunity 1999;11:253–61.

106. Hymowitz SG, O’Connell MP, Ultsch MH, Hurst A, Totpal K, Ashkenazi A, de Vos AM, Kelley RF. A unique zinc-binding site

revealed by a high-resolution X-ray structure of homotrimeric Apo2L/TRAIL. Biochemistry 2000;39:633–40.

107. Lam J, Nelson CA, Ross FP, Teitelbaum SL, Fremont DH. Crystal structure of the TRANCE/RANKL cytokine reveals determinants of receptor-ligand specificity. J Clin Invest 2001;108:971–9.

108. Ito S, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T. Crystal structure of the extracellular domain of mouse RANK ligand at 2.2-A resolution. J Biol Chem 2002;277:6631–6.

109. Jin T, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T. X-ray crystal structure of TNF ligand family member TL1A at 2.1 Å. Biochem Biophys Res Commun 2007;364:1–6.

110. Zhou Z, Wakabayashi K, Ubukata O, Hayashi S, Okada F, Hata T. Human glucocorticoid-induced TNF receptor ligand regulates its signaling activity through multiple oligomerization states. Proc Natl Acad Sci USA 2008;105:5465–70.

111. Naismith JH, Devine TQ, Brandhuber BJ, Sprang SR. Crystallographic evidence for dimerization of unliganded tumor necrosis factor receptor. J Biol Chem 1995;270:13,303–7.

112. Naismith JH, Devine TQ, Kohno T, Sprang SR. Structures of the extracellular domain of the type I tumor necrosis factor receptor. Structure 1996;4:1251–62.

113. Fellouse FA, Li B, Compaan DM, Peden AA, Hymowitz SG, Sidhu SS. Molecular recognition by a binary code. J Mol Biol 2005;348:1153–62.

114. Li B, Russell SJ, Compaan DM, Totpal K, Marsters SA, Ashkenazi A, Cochran AG, Hymowitz SG, Sidhu SS. Activation of the proapoptotic death receptor DR5 by oligomeric peptide and anti-body agonists. J Mol Biol 2006;361:522–36.

115. Carfi A, Willis SH, Whitbeck JC, Krummenacher C, Cohen GH, Eisenberg RJ, Wiley DC. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Mol Cell 2001;8:169–79.

116. Compaan DM, Gonzalez LC, Tom I, Loyet KM, Eaton D, Hymowitz SG. Attenuating lymphocyte activity: the crystal structure of the BTLA–HVEM complex. J Biol Chem 2005;280:39,553–61.

117. He XL, Garcia KC. Structure of nerve growth factor complexed with the shared neurotrophin receptor p75. Science 2004;304:870–5.

118. Gong Y, Cao P, Yu HJ, Jiang T. Crystal structure of the neurotrophin-3 and p75NTR symmetrical complex. Nature 2008;454:789–93.


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