Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Tedbury, Philip R.; Novikova, Mariia; Ablan, Sherimay D.; Freed, Eric O.

doi:10.1073/pnas.1516618113

Cited by 75 publications

(136 citation statements)

References 51 publications

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“…The above-described results suggest that ⌬CT Env proteins assemble passively into HIV-1 virions, whereas WT Env proteins require a direct or indirect interaction with MA for virion incorporation (17,18,(22)(23)(24)(25). Because of the unusual length of the HIV-1 Env CT, one can speculate that WT Env trimers are hindered from assembling into lattices organized by PrGag proteins …”

Section: The Hiv-1 Env Proteins Assemble As Trimers and Incorporatiomentioning

confidence: 99%

“…The same is not true for the WT HIV-1 Env protein (17,18). However, HIV-1 Env proteins that carry deletions of the long Env cytoplasmic tail (CT) can be assembled efficiently into either WT or ⌬MA HIV-1 particles (18), at least in cell types that permit the efficient cell surface localization of ⌬CT Env proteins (32, 33).The above-described results suggest that ⌬CT Env proteins assemble passively into HIV-1 virions, whereas WT Env proteins require a direct or indirect interaction with MA for virion incorporation (17,18,(22)(23)(24)(25). Because of the unusual length of the HIV-1 Env CT, one can speculate that WT Env trimers are hindered from assembling into lattices organized by PrGag proteins …”

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confidence: 99%

“…A second role of HIV-1 MA is to facilitate the incorporation of envelope (Env) proteins into virions (22)(23)(24)(25). How MA accomplishes this is complicated.…”

mentioning

confidence: 99%

“…HIV-1 MA has a propensity to form trimers (22)(23)(24)(25)(34)(35)(36), and mutations of residues at the spokes of those trimers (such as 12LE, 16EK, 30LE, 34VE, and 98EV) (Fig. 1A) have been shown to impair WT HIV-1 Env virion incorporation (22)(23)(24)(25)37). MA also has been shown to assemble in vitro in two forms of hexamer lattices, and in both lattices, residues 12, 16, 30, 34, and 98 point toward hexamer centers ( Fig.…”

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confidence: 99%

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Trimer Enhancement Mutation Effects on HIV-1 Matrix Protein Binding Activities

Alfadhli

Mack

Ritchie

et al. 2016

J Virol

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The HIV-1 matrix (MA) protein is the amino-terminal domain of the HIV-1 precursor Gag (Pr55Gag) protein. MA binds to membranes and RNAs, helps transport Pr55Gag proteins to virus assembly sites at the plasma membranes of infected cells, and facilitates the incorporation of HIV-1 envelope (Env) proteins into virions by virtue of an interaction with the Env protein cytoplasmic tails (CTs). MA has been shown to crystallize as a trimer and to organize on membranes in hexamer lattices. MA mutations that localize to residues near the ends of trimer spokes have been observed to impair Env protein assembly into virus particles, and several of these are suppressed by the 62QR mutation at the hubs of trimer interfaces. We have examined the binding activities of wild-type (WT) MA and 62QR MA variants and found that the 62QR mutation stabilized MA trimers but did not alter the way MA proteins organized on membranes. Relative to WT MA, the 62QR protein showed small effects on membrane and RNA binding. However, 62QR proteins bound significantly better to Env CTs than their WT counterparts, and CT binding efficiencies correlated with trimerization efficiencies. Our data suggest a model in which multivalent binding of trimeric HIV-1 Env proteins to MA trimers contributes to the process of Env virion incorporation. T he matrix (MA) domain of the human immunodeficiency type 1 (HIV-1) precursor Gag (Pr55Gag) protein serves several assembly-related functions. One role is to direct Pr55Gag proteins to assembly sites at cell plasma membranes (PMs) that are enriched for phosphatidylinositol-4,5-bisphosphate (PI[4,5]P2) and cholesterol (1-8). This function is accomplished in part by virtue of an amino-terminal myristate moiety and, in part, through direct binding to PI(4,5)P2 (1). Evidence indicates that the PI(4,5)P2-binding site on MA overlaps a binding site for RNA, which suggests a chaperone model in which MA-RNA binding protects the MA domain of Pr55Gag from associating with inappropriate intracellular membranes prior to delivery to the PI(4,5)P2-rich PM assembly sites (9-16). In some experimental systems, it has been shown that Pr55Gag proteins with MA deletions (⌬MA) or swaps of MA with other membrane binding domains are capable of directing the assembly of conditionally infectious viruses, but in these cases, assembly and replication efficiencies have tended to be compromised (17)(18)(19)(20)(21). IMPORTANCE The HIV-1 Env proteins assemble as trimers, and incorporation of the proteins into virus particles requires an interaction of EnvA second role of HIV-1 MA is to facilitate the incorporation of envelope (Env) proteins into virions (22-25). How MA accomplishes this is complicated. One confounding issue is that some cell surface proteins can be assembled into HIV-1 particles in what appears to be a passive fashion (26). Indeed, this is how glycoproteins from other viruses can pseudotype with the cores of HIV-1 (17, 27-31). Presumably, PM proteins that localize to HIV-1 assembly sites can be incorporated into viruses as...

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Section: The Hiv-1 Env Proteins Assemble As Trimers and Incorporatiomentioning

confidence: 99%

mentioning

confidence: 99%

“…A second role of HIV-1 MA is to facilitate the incorporation of envelope (Env) proteins into virions (22)(23)(24)(25). How MA accomplishes this is complicated.…”

mentioning

confidence: 99%

mentioning

confidence: 99%

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Trimer Enhancement Mutation Effects on HIV-1 Matrix Protein Binding Activities

Alfadhli

Mack

Ritchie

et al. 2016

J Virol

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“…The presence of Gag decreases the rate of Env internalization by targeting the internalization motif in the HIV-1 GP41CT (295). (v) Matrix trimerization that builds a lattice capable of accommodating the GP41CT is crucial for Env packaging (296). (vi) Human proteins may exert an impact on the matrix Gag -GP41 Env interaction.…”

Section: Lymphocytes (292) (Iii) Given That Gag and Env Proteins Arementioning

confidence: 99%

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Clercq

2016

Microbiol Mol Biol Rev

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SUMMARYThe HIV genome encodes a small number of viral proteins (i.e., 16), invariably establishing cooperative associations among HIV proteins and between HIV and host proteins, to invade host cells and hijack their internal machineries. As a known example, the HIV envelope glycoprotein GP120 is closely associated with GP41 for viral entry. From a genome-wide perspective, a hypothesis can be worked out to determine whether 16 HIV proteins could develop 120 possible pairwise associations either by physical interactions or by functional associations mediated via HIV or host molecules. Here, we present the first systematic review of experimental evidence on HIV genome-wide protein associations using a large body of publications accumulated over the past 3 decades. Of 120 possible pairwise associations between 16 HIV proteins, at least 34 physical interactions and 17 functional associations have been identified. To achieve efficient viral replication and infection, HIV protein associations play essential roles (e.g., cleavage, inhibition, and activation) during the HIV life cycle. In either a dispensable or an indispensable manner, each HIV protein collaborates with another viral protein to accomplish specific activities that precisely take place at the proper stages of the HIV life cycle. In addition, HIV genome-wide protein associations have an impact on anti-HIV inhibitors due to the extensive cross talk between drug-inhibited proteins and other HIV proteins. Overall, this study presents for the first time a comprehensive overview of HIV genome-wide protein associations, highlighting meticulous collaborations between all viral proteins during the HIV life cycle.

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Characterization and epitope mapping of a panel of monoclonal antibodies against HIV‐1 matrix protein

Zhang

Feng

Bai

et al. 2018

Biotech and App Biochem

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The HIV-1 Gag precursor protein (p55) is the main structural protein comprising the matrix (MA/p17), capsid (CA/p24), and nucleocapsid (NC/p7) proteins, and is uniquely responsible for virion assembly within the virus life cycle. The MA protein plays a critical role in plasma membrane targeting and envelope glycoprotein (Env) uptake during virion assembly. Yet, when viral infection occurs, the MA protein may also be involved in virion uncoating, dissociating from the plasma membrane, and participating in the nuclear importation process. Thus, the MA protein contains a reversibly membrane-binding signal and varied conformation to govern its subcellular localization and biological functions. However, these purported different conformations of the MA protein during assembly are poorly understood, especially in terms of its function as a component of the precursor protein. In this study, we characterized a panel of monoclonal antibodies against MA that showed discrete reactivity to p55, an intermediate (p41), and the final p17 mature form. We suggest that these antibodies could be used to track the different conformations of MA during the HIV-1 life cycle, particularly during HIV-1 assembly and maturation, and contribute to structure determination of MA or MA precursors. These antibodies would also have clinical value, including serving for therapeutic strategy to interfere AIDS progression, reagent in diagnostic kit for the detection of virion-free p17 or p17 derived from virion lysate.

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Biochemical evidence of a role for matrix trimerization in HIV-1 envelope glycoprotein incorporation

Cited by 75 publications

References 51 publications

Trimer Enhancement Mutation Effects on HIV-1 Matrix Protein Binding Activities

Trimer Enhancement Mutation Effects on HIV-1 Matrix Protein Binding Activities

HIV Genome-Wide Protein Associations: a Review of 30 Years of Research

Characterization and epitope mapping of a panel of monoclonal antibodies against HIV‐1 matrix protein

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