Gp41 - ENV Glycoprotein 41

Gp41 is a transmembrane glycoprotein that transverses the lipid bilayer of the virion.



Homology Model created using PDB structures: 1envA.pdb, 2ezpB.pdb, 2ezrA.pdb, 2ezpC.pdb, 2ezrC.pdb

Key web links:
ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB: 1ENV-A, 2EZP-B/C, 2ERZ-A/C (HIV-1 gp41)
UniProt: P04578 (HIV-1 HXB2 ENV)
Chime Tutorial: not available
HIV-1/Human Protein Interaction DB: HIV-1 Env
Los Alamos HIV structure DB: HIV ENV
EMBL: K03455 [EMBL/GenBank/DDBJ]


Isoforms:

  • Gp41 - transmembrane glycoprotein (345 amino acids)

Function:

  • Non-covalently bound to gp120.
  • Mediates the fusion of viral and cellular membranes .

Localization:

  • Cell plasma membrane
  • Virion envelope

Additional Information:

  • Late timing of expression.
  • The gp120-gp41 complex occurs as a trimer on the surface of the virion.
  • Contains an N-terminal fusogenic domain, which mediates the fusion of viral and cellular membranes .
  • The interaction between gp120 with cellular receptors trigger gp41 to extend (forming a pre-hairpin intermediate), which interacts with the plasma membrane of the target cell.
  • The extended pre-hairpin intermediate collapses into a trimer-of-hairpins structure that brings the amino- and carboxyl-terminal regions of the gp41 extracellular domain into close proximity.
  • Bringing the amino- and carboxyl-terminal regions of the extracellular domain together forces the membranes together in a manner that facilitates membrane fusion.


Gp41 Function & Host-Virus Protein Interactions:[TOP]




Interactions highlighted in the image:


Potential interactions (not in the image):


  • HIV gp41 interacts with the HIV Gag polyprotein prior to its incorporation into nascent virions.
  • HIV gp41 interacts non-covalently with gp120.
  • HIV gp41 interacts with the host cellular membrane.


Genomic Location & Protein Sequence: [TOP]

HIV-1 (HXB2):

          10         20         30         40         50         60         70         80         90        100
| | | | | | | | | |
AVGIGALFLG FLGAAGSTMG AASMTLTVQA RQLLSGIVQQ QNNLLRAIEA QQHLLQLTVW GIKQLQARIL AVERYLKDQQ LLGIWGCSGK LICTTAVPWN
110 120 130 140 150 160 170 180 190 200
| | | | | | | | | |
ASWSNKSLEQ IWNHTTWMEW DREINNYTSL IHSLIEESQN QQEKNEQELL ELDKWASLWN WFNITNWLWY IKLFIMIVGG LVGLRIVFAV LSIVNRVRQG
210 220 230 240 250 260 270 280 290 300
| | | | | | | | | |
YSPLSFQTHL PTPRGPDRPE GIEEEGGERD RDRSIRLVNG SLALIWDDLR SLCLFSYHRL RDLLLIVTRI VELLGRRGWE ALKYWWNLLQ YWSQELKNSA
310 320 330 340
| | | |
VSLLNATAIA VAEGTDRVIE VVQGACRAIR HIPRRIRQGL ERILL
[download in fasta format]

Length: 345 amino acids
Molecular Weight: 39558 Da
Theoretical pI: 8.92
Position relative to Env protein: 512 - 856


Protein Domains/Folds/Motifs: [TOP]

InterPro signature for Envelope Polyprotein gp41 - IPR000328

Contains an N-terminal fusogenic domain, which mediates the fusion of viral and cellular membranes .


Secondary Structure prediction:

Transmembrane Regions - tmhmm:


Low Complexity Regions - seg:


Coiled-coil Region - ncoils:


Antigenic Sites - EMBOSS:




Predicted Motifs: Printer-friendly version

N-glycosylation:
N-myristoylation:
Amidation:
Protein kinase C:
Casein kinase II:
Tyrosine kinase:
cAMP / cGMP kinase:
Cell attachment motif:
Asp Protease motif:
Asp Prot Retro motif:
Cysteine-rich Region:
Tryptophan-rich Region:
Zinc-finger CCHC motif:
Leucine Zipper motif:


See Stanford University HIV Drug Resistance Database


See ViralZone HIV Drug Pages


Mechanism of Action:


Viral entry describes a complex process that involves various steps, including the fusion of the viral membrane to the host cellular membrane.
Currently, there is only one fusion inhibitor that has been approved for HIV treatment, Enfuviritide.
This 36 amino acid polypeptide binds to the haptad repeat (HR) regions of the gp41 viral protein and engages in a coil-coil interaction.
This interaction prevents the virus particle from attaching to the host cell membrane and thus, prevents the entry and infection of HIV.


Drug Resistance Mutations:


Fusion Inhibitor:
Position Mutation Additional Information Drugs Affected Reference
G36 D, E, V, S G36D/E mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
I37 V Enfuviritide
V38 E, A, M, G V38E/A mutations are associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
Q40 H Mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
N42 T, S N42S occurs in ~15% of viruses from Enfuviritide-naive patients and does not decrease drug susceptibility. Enfuviritide
N43 D, K, S N43D mutation is associated with a large decrease in Enfuviritide susceptibility (>10 fold). Enfuviritide
L44 M Enfuviritide
L45 M Enfuviritide
Primary and Secondary Database Entries: [TOP]

Identifiers:



ViralZone: HIV-1, HIV replication cycle, HIV resource
PDB/MMDB: Search for HIV-1 & gp41

UniProt: P04578 (HIV-1 HXB2 ENV)
EMBL: K03455; AAB50262.1 [EMBL/GenBank/DDBJ]

InterPro: IPR000328 - gp41 family
Pfam: PF00517 - gp41 family
Prints: none
SCOP: SSF56349 - DNA breaking-rejoining enzymes / SSF56425 - Succinate dehydrogenase catalytic domain
BLOCKS: P04578
Prosite: P04578
ProtoNet: P04578
Database of Interacting Proteins: P04578
ModBase: P04578
HIV-1/Human Protein Interaction DB: HIV-1 Env
HIV-1 Sequence Database Los Alamos HIV Sequence Database

PDB:




Reviews and References: [TOP]

Cite the resource by citing the following paper:
Doherty R et al. BioAfrica's HIV-1 Proteomics Resource: Combining protein data with bioinformatics tools. Retrovirology (2005), 9;2(1):18.

1 - HIV Sequence Compendium 2000
Kuiken CL, Foley B, Hahn B, Korber B, Marx PA, McCutchan F, Mellors JW, Mullins JI, Sodroski J, Wolinksy S.
Theoretical Biol. & Biophys. Group, Los Alamos Nat Lab, LA-UR 01-3860 [Read it online: Compendium]
2 - Retroviruses
Coffin JM, Hughes SH, Varmus HE.
CD-ROM ed. (2002) Cold Spring Harbor Laboratory Press [Read it online: NCBI Bookshelf]
3 - A CD4 domain important for HIV-mediated syncytium formation lies outside the virus binding site.
Camerini D, Seed B.
Cell 60: 747-754 (1990) [pubmed: 2107024]
4 - [viral/plasma membrane fusion activity of gp41 core domain] The crystal structure of the SIV gp41
ectodomain at 1.47 A resolution.
Yang ZN, Mueser TC, Kaufman J, Stahl SJ, Wingfield PT, Hyde CC.
J Struct Biol 126(2): 131-144 (1999) [pubmed: 10388624]
5 - Binding of HTLV-III/LAV to T4+ T cells by a complex of the 110K viral protein and the T4 molecule.
McDougal JS, Kennedy MS, Sligh JM, Cort SP, Mawle A, Nicholson JK.
Science 231(4736):382-5 (1986) [pubmed: 3001934]
6 - CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5.
Wu L, Gerard NP, Wyatt R, Choe H, Parolin C, Ruffing N, Borsetti A, Cardoso AA, Desjardin E, Newman W, Gerard C, Sodroski J.
Nature 384(6605):179-83 (1996) [pubmed: 8906795]
7 - Drug resistance mutations for surveillance of transmitted HIV-1 drug-resistance: 2009 update.
Bennett DE, Camacho RJ, Otelea D, Kuritzkes DR, Fleury H, Kiuchi M, Heneine W, Kantor R, Jordan MR, Schapiro JM, Vandamme AM, Sandstrom P, Boucher CA, van de Vijver D, Rhee SY, Liu TF, Pillay D, Shafer RW.
PLoS One 4(3):e4724 (2009) [pubmed: 19266092]
8 - Characterization of envelope glycoprotein gp41 genotype and phenotypic susceptibility to enfuvirtide at baseline and on treatment in the phase III clinical trials TORO-1 and TORO-2.
Melby T, Sista P, DeMasi R, Kirkland T, Roberts N, Salgo M, Heilek-Snyder G, Cammack N, Matthews TJ, Greenberg ML.
AIDS Res Hum Retroviruses 22(5):375-85 (2006) [pubmed: 16706613]



Thanks to ViralZone at the Swiss Institute of Bioinformatics (SIB) for allowing the use of their images on bioafrica.net.
Page last updated by Megan Druce, Paula Sommer and Tulio de Oliveira (UKZN/Africa Centre) & Philippe Le Mercier, Chantal Hulo and Patrick Masson (SIB/ViralZone).