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Human immunodeficiency virus type 1 matrix protein assembles on membranes as a hexamer.

ABSTRACT: The membrane-binding matrix (MA) domain of the human immunodeficiency virus type 1 (HIV-1) structural precursor Gag (PrGag) protein oligomerizes in solution as a trimer and crystallizes in three dimensions as a trimer unit. A number of models have been proposed to explain how MA trimers might align with respect to PrGag capsid (CA) N-terminal domains (NTDs), which assemble hexagonal lattices. We have examined the binding of naturally myristoylated HIV-1 matrix (MyrMA) and matrix plus capsid (MyrMACA) proteins on membranes in vitro. Unexpectedly, MyrMA and MyrMACA proteins both assembled hexagonal cage lattices on phosphatidylserine-cholesterol membranes. Membrane-bound MyrMA proteins did not organize into trimer units but, rather, organized into hexamer rings. Our results yield a model in which MA domains stack directly above NTD hexamers in immature particles, and they have implications for HIV assembly and interactions between MA and the viral membrane glycoproteins.

SUBMITTER: Alfadhli A

PROVIDER: S-EPMC1797500 | biostudies-literature | 2007 Feb

REPOSITORIES: biostudies-literature

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Human immunodeficiency virus type 1 matrix protein assembles on membranes as a hexamer.

Alfadhli Ayna A Huseby Doug D Kapit Eliot E Colman Dalbinder D Barklis Eric E

Journal of virology 20061115 3

The membrane-binding matrix (MA) domain of the human immunodeficiency virus type 1 (HIV-1) structural precursor Gag (PrGag) protein oligomerizes in solution as a trimer and crystallizes in three dimensions as a trimer unit. A number of models have been proposed to explain how MA trimers might align with respect to PrGag capsid (CA) N-terminal domains (NTDs), which assemble hexagonal lattices. We have examined the binding of naturally myristoylated HIV-1 matrix (MyrMA) and matrix plus capsid (Myr ...[more]

PMID: 17108052

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Project description:UnlabelledExogenous HIV-1 matrix protein p17 (p17) deregulates the function of different cells after its N-terminal loop (AT20) binding to the chemokine receptors CXCR1 and CXCR2. One site within AT20 has been recently found to be the major determinant of viral fitness following transmission of simian immunodeficiency virus (SIV) to the human host. Therefore, we sought to determine whether SIV matrix protein (MA) was already capable of interacting with CXCR1 and CXCR2 and mimic p17 biological activities rather than this being a newly acquired function during host adaptation. We show here that SIV MA binds with the same affinity of p17 to CXCR1 and CXCR2 and displays both p17 proangiogenic on human primary endothelial cells and chemotactic activity on human primary monocytes and B cells. However, SIV MA exhibited a higher degree of plasticity than p17 in the C terminus, a region known to play a role in modulating B cell growth. Indeed, in contrast to p17, SIV MA was found to activate the phosphatidylinositol 3-kinase/Akt signaling pathway and strongly promote B cell proliferation and clonogenic activity. Interestingly, we have recently highlighted the existence of a Ugandan HIV-1 strain-derived p17 variant (S75X) with the same B cell growth-promoting activity of SIV MA. Computational modeling allowed us to hypothesize an altered C terminus/core region interaction behind SIV MA and S75X activity. Our findings suggest the appearance of a structural constraint in the p17 C terminus that controls B cell growth, which may help to elucidate the evolutionary trajectory of HIV-1.ImportanceThe HIV-1 matrix protein p17 (p17) deregulates the biological activities of different cells after binding to the chemokine receptors CXCR1 and CXCR2. The p17 functional domain responsible for receptors interaction includes an amino acid which is considered the major determinant of SIV replication in humans. Therefore, we sought to determine whether SIV matrix protein (SIV MA) already had the ability to bind to both chemokine receptors rather than being a function newly acquired during host adaptation. We show here that SIV MA binds to CXCR1 and CXCR2 and fully mimics the p17 proangiogenic and chemokine activity. However, it differs from p17 in its ability to signal into B cells and promote B cell growth and clonogenicity. Computational analysis suggests that the accumulation of mutations in the C-terminal region may have led to a further SIV MA adaptation to the human host. This finding in turn sheds light on the evolutionary trajectory of HIV-1.

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Human immunodeficiency virus type 1 matrix protein assembles on membranes as a hexamer.

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Human immunodeficiency virus type 1 matrix protein assembles on membranes as a hexamer.

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