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gp120 and gp41 HIV envelope proteins (transglutaminase substrates)

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gp120 & gp41 are two proteins (glycoproteins) located on the surface of a virus called Human immunodeficiency virus (HIV).

gp120:
gp120 is the portion of the HIV envelope protein which is on the surface of the virus (Berman 1994).
gp120 is known to possess the CD4 binding domain by which HIV attaches to its target cells (Berman 1994).

gp41:
The transmembrane protein gp41 contains several glutamine residues, 75% of which are located on the outer surface of the virus.

INVASION:
Despite being extensively studied, the entry process of HIV, the causative agent of AIDS remains a debated issue.
It has been postulated that, after gp120 binding, HIV enters the cell either by direct fusion of the virus envelope with the plasma membrane or by receptor-mediated endocytosis of a CD4-HIV complex.

TWO WAYS OF HIV INVASION:

1) HIV WAY ONE: FUSION WITH PLASMA MEMBRANE
It has long been thought that productive entry of HIV occurs via direct fusion of the viral envelope with the host cell plasma membrane.
DIRECT FUSION FACTS:
- One key piece of evidence for an endocytic-independent entry is the observation that infection is insensitive to neutralisation of endosomal pH. In fact, blocking endosome acidification was in some cases seen to augment viral infection, perhaps by sparing particles from lysosomal degredation.
- CD4 endocytosis was not required for HIV entry, suggesting that endocytosed particles were degraded by host cell lysosomes.

2) HIV WAY TWO: RECEPTOR MEDIATED ENDOCYTOSIS:
Whilst the clathrin-mediated entry pathway has been documented for almost as long as the classical plasma membrane entry mechanism, it has only recently been confirmed that this route offers a productive entry pathway for HIV (Daecke 2005) (24).
Recent data may even suggest that clathrin-mediated HIV entry is the only productive pathway for infection (Miyauchi et al. 2009) (24).
ENDOCYTOSIS FACTS:
- EM studies have shown internalised virions in membrane-bound vesicles. Moreover, the rates of entry and uncoating of radio labelled virions in the human T-lymphoid cell line CEM were consistent with a receptor-mediated mechanism of entry.
- Live cell imaging has demonstrated that HIV fusion at the plasma membrane did not proceed further than mixing of lipids and could therefore not lead to productive infection.

gp120 & gp41 & TRANSGLUTAMINASE:
gp120 & gp41 ARE TRANSGLUTAMINASE SUBSTRATES:
Conversion by proteolysis, of gp160 into gp120 and gp41, exposes amino-acceptor (acyl donor) glutaminyl residues not only in gp120 but also in gp41.

gp120 & gp41 are both transglutaminase substrates.

http://www.ncbi.nlm.nih.gov/pubmed/8104907
http://www.ncbi.nlm.nih.gov/pubmed/7688299

TRANSGLUTAMINASE CROSSLINKING BETWEEN HIV AND HUMAN PROTEINS:
gp41 could cross-link to receptor(s) occurring on HIV-target cells and/or gp120 with both glutaminyl and lysyl residues.
Transglutaminase reactive sites in gp41 have been proposed for possible cross-linking reactions with gp120, CD4 or other receptor(s) occurring on the surface of HIV-target cells.
An extracellular or membrane-associated molecular form of transglutaminase could cross-link the virus env glycoproteins to each other and/or to CD4 or some different protein receptor occurring on the surface of the HIV-target cell.

TRANSGLUTAMINASE & CLATHRIN MEDIATED ENTRY INTO HOST CELLS:
Several functions have been ascribed to transglutaminases including receptor-mediated endocytosis.
The possibility that TGase catalyzes the formation of a covalent bond between protein(s) of the HIV envelope (env) and protein(s) present on the membrane of HIV-target cells.
Possible role for human-immunodeficiency-virus (HIV) internalization, by some molecular forms of transglutaminase either occurring extracellularly or associated to the membrane of the HIV-target cells.
Possible role for transglutaminase in virus entry into host cells, via receptor-mediated endocytosis, and/or in HIV-induced CD4+ T-cell depletion via apoptosis.
In conclusion, the experimental evidence that soluble gp120 and gp41 can act as TGase substrates in vitro supports the notion that the enzyme could participate in the process of HIV entry into the host cells.
Transglutaminase may play a role in the process of virus internalization by cross-linking HIV env glycoproteins to specific receptor(s) occurring on the target-cell surface.
TGase-catalyzed covalent modification of gp120 could influence the ability of HIV both to penetrate inside the cells and to infect them.
A role played in HIV internalization by some molecular forms of the enzyme, either membrane-associated or occurring outside of the cell (such as blood plasma Factor XIII), cannot be ruled out and deserves further investigation.

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