Asim Farooq

Inhibition of TGF ReceptorsFKBP12 Binding

ASAB - NUST

Introduction TGFβ family plays a central role in controlling

tissue development and homeostasis Their activation, signaling and deactivation is

carefully co-ordinated Serine Threonine kinases, two subunits(I & II),

having a phosphorylating GS domain, RII is a primary receptor and RI is a signal transducer

Mediator protein is SMAD, which accumulates in nucleus and binds to SNPs and transcriptional regulators

Continued Type I receptors have ability to remain activated

in absence of ligand or type II receptors FKBP12 binds to the intracellular domain of

receptor FKBP12 proteins have prolyl isomerase activity,

bind to the Ca2+/calmodulin-dependent protein phosphatase calcineurin and inhibit its ability to mediate T-cell activation, bind to the ryanodine receptor and the inositol 1,4,5-triphosphate receptor, stabilizing the calcium channeling

Receptor Binding FKBP12 interacts with the GS domain of TBR1 The conserved sequence of binding is

T185TSGSGSGLP Missense mutations abolish the receptor

interaction (L193G & P194K) Mutations other than this does not have any

effect on binding capability FKBP12 recognizes a specific structure within

the GS domain that includes the Leu–Pro motif.

FKBP12 Protects Against Leaky TGF Receptor Activation

Mutations in TBR1 result in elevated signaling Overexpression of FKBP12 results in complete

inhibition of signaling Identification of Leu193–Pro as a FKBP12-

binding site argue that the interaction involves the FKBP12 catalytic site

Mechanism of Inhibition FBKP12 inhibits phosphorylation of TBR-I by

TBR-IIHOW???

Overexpression of FKBP12 inhibits ligand-induced TBR-I phosphorylation, whereas the overexpression of mutants defective in TBR-I binding does not

Rapamycin augments TbR-I phosphorylation and reverses the inhibitory effect of overexpressed FKBP12

Continued… FKBP12 binding to this site is likely to hinder

the entry of the phosphorylation sites into the catalytic center of the TBR-II kinase, thus protecting TBR-I from activation during ligand-independent interactions with TBR-II.

In normal physiological conditions, ligand binding removes FKBP12 and receptor is activated to carry out down stream signaling