HIV-1 GP120

By:Christopher YapSpenser Auclerc Michael English

Glycoproteins are proteins (amino acid chains) that have covalently attached oligosaccharides side chains (linked carbohydrate sugars).

Oligosaccharides are typically oxygen or nitrogen linked to amino acids in proteins.

Figure 1:

Linked Carbohydrate Sugars

Protein Amino Acid Chain

Multiple carbohydrate sugars can be N-linked to asparagine or O-linked serine and threonine.

Wales Jimmy, Larry Sanger et al. “Glycoprotein.” Wikipedia. March, 2015. Wikimedia Foundation. 3 March 2015 < https://en.wikipedia.org/wiki/Glycoprotein >

Motif of glycoprotein

Motif of glycoprotein An asparagine amino acid in a protein can accept a carbohydrate side chain

only if it is part of a specific sequence.

Asn - X - Ser or Asn - X - Thr The X can be any amino acid except proline. This pattern allows, potential glycosylation sites to be detected based on a

protein's amino acid sequence. However, not all potential sites are glycosylated. Which sites are glycosylated depends on the cell type that expresses the

glycoprotein. Amino Acid Figure 2:

Glycosidic Nitrogen Bond Glycosidic Oxygen Bond Carbohydrate Sugar

Berg Jeremy M., John L. Tymoczko and Lubert Stryer. Biochemistry 7th Ed. New York: W. H. Freeman and Company, 2011. Page 330.

Motif of glycoprotein All N-linked oligosaccharides have in common a 5-saccharide

core consisting of 3 mannose and 2 N-acetylglucosamine residues.

Other sugars are attached to this core to form a great variety of oligosaccharide patterns found in glycoproteins.

Figure 3:

Common 5-Saccharide Core

Berg Jeremy M., John L. Tymoczko and Lubert Stryer. Biochemistry 7th Ed. New York: W. H. Freeman and Company, 2011. Page 330.

Glycoproteins are Information Molecules

Glycoproteins serve as sites of protein to protein interaction They are commonly found on the plasma membrane of cells. Glycoproteins are used by cells as recognition sites for a class of

proteins called glycan binding proteins. Glycan binding proteins are highly selective and facilitate cell to cell

interactions. They typically have two or more carbohydrate binding sites. These sites bind non-covalently to multiple carbohydrates and

multiple weak interactions builds to a composite strong bond.

Glycoprotein GP120 GP120 is a 120kDa glycoprotein that is exposed on the surface

on the envelope of HIV viruses. Envelope Glycoprotein GP-120 is a viral matrix protein and is a

structural protein that links the viral envelope to the virus core. GP120 plays a central role in allowing HIV phages to recognize

CD4 glycoproteins on the surface of immune cells.

Structure of GP120 According to McLellan et al., much of the success of

the HIV virus is due to variable regions within GP120. This is especially true for

variable regions 1 and 2 (V1/V2). These regions are protected by N-linked

carbohydrates. The V1/V2 region forms a four stranded β-sheet

domain. This region greatly enhances the ability to avoid

detection by the hosts immune system.

Structure of GP120 The graphic to the right shows

GP120 in it’s tertiary form The light blue portion is the Inner

Domain The red portion is the Outer

Domain The pink portion is the Bridge

Sheet connecting the two domains The Green portions are Cysteine

residues that form intrachain disulfide linkages. These linkages are flexible allowing for conformational changes within the bound protein.

These linkages were first discovered through X-Ray diffraction.

Homologues of GP120

Homologous structures are the result of a shared origin or convergence due to a similar function.

According to Luisa et al. sequence 160-170 of GP120 is homologous to snake curare-mimetic neurotoxins and glycoproteins present on the envelope of the rabies virus.

This sequence allows GP120, snake venoms and rabies to bind to nicotinic receptors.

Rabies virus cross-section with glycoproteins

Structural Mutations of GP120

The evolution of GP120 is of particular interest to AIDS research. Variability in GP120 increases the fitness of the virus and is highly

selected. Diversity in the HIV env gene that codes for GP120 increases 1 to 2%

each year.

HIV viruses fit a Quasispecies Model

A quasispecies is a rapidly mutating organism that gives rise to competing genotypes. The mutant offspring may out compete the parents.

This often occurs after transmission of the HIV virus. In the HIV-1 specific regions of GP120 are targeted by antibodies. These regions tend to mutate rapidly and are highly variable.

Targeting GP120 for Treatment Enfuviritide is a drug that targets GP120

for treatment of HIV. Enfuviritide prevents conformational

changes that allow GP41 to enter the host cell membrane.

Mutations to GP120 have been found to increase resistance to Enfuviritide.

Enfuviritide Resistance• The table below shows possible mutations at different

positions on GP120, all of which greatly decrease Enfuviritide susceptibility.

Works Cited

Berg Jeremy M., John L. Tymoczko and Lubert Stryer. Biochemistry. New York: W. H. Freeman and Company, 2011.

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2642736/Wales Jimmy, Larry Sanger et al. “Erythropoiesis.” Wikipedia. Sep., 2014. Wikimedia Foundation. 3 March 2015

Wales Jimmy, Larry Sanger et al. “Glycoprotein.” Wikipedia. March, 2015. Wikimedia Foundation. 3 March 2015

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