Cited by 227HIV Research and TreatmentLipid Membrane Structure and BehaviorT-cell and Retrovirus Studies

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Differential membrane binding of the human immunodeficiency virus type 1 matrix protein

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Zhou, W, Resh, M D·1996·Journal of Virology

DOI 10.1128/jvi.70.12.8540-8548.1996PMC PMC190946

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Abstract

The human immunodeficiency virus type 1 matrix protein (p17MA) plays a central role at both the early and late stages of the virus life cycle. During viral assembly, the p17MA domain of Pr55gag promotes membrane association, which is essential for the formation of viral particles. When viral infection occurs, the mature p17MA dissociates from the plasma membrane and participates in the nuclear targeting process. Thus, p17MA contains a reversible membrane binding signal to govern its differential subcellular localization and biological functions. We previously identified a membrane binding signal within the amino-terminal 31 amino acids of the matrix domain of human immunodeficiency virus type 1 Gag, consisting of myristate and a highly basic region (W. Zhou, L. J. Parent, J. W. Wills, and M. D. Resh, J. Virol. 68:2556-2569, 1994). Here we show that exposure of this membrane binding signal is regulated in different Gag protein contexts. Within full-length Pr55gag, the membrane targeting signal is exposed and can direct Pr55gag as well as heterologous proteins to the plasma membrane. However, in the context of p17MA alone, this signal is hidden and unable to confer plasma membrane binding. To investigate the molecular mechanism for regulation of membrane binding, a series of deletions within p17MA was generated by sequentially removing alpha-helical regions defined by the nuclear magnetic resonance structure. Removal of the last alpha helix (amino acids 97 to 109) of p17MA was associated with enhancement of binding to biological membranes in vitro and in vivo. Liposome binding experiments indicated that the C-terminal region of p17MA exerts a negative effect on the N-terminal MA membrane targeting domain by sequestering the myristate signal. We propose that mature p17MA adopts a conformation different from that of the p17MA domain within Pr55gag and present evidence to support this hypothesis. It is likely that such a conformational change results in an N-terminal myristyl switch which governs differential membrane binding.

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Tsg101 can replace Nedd4 function in ASV Gag release but not membrane targeting
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Background
Type D Retrovirus Capsid Assembly and Release Are Active Events Requiring ATP
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“In concert with a myristic acid moiety at the N terminus, this domain is important for Gag targeting to the PM during virus assembly (26, 36, 58, 62, 73).”
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Background
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Background
Discovery of a small-molecule antiviral targeting the HIV-1 matrix protein
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Background
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Background
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Background
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“HIV-1 model (22, 34, 46), the late association between”
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Background
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Self-citation
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“Substitutions of the MA N-terminal residues that prevent the acylation by myristoyl transferase drastically reduces the membrane binding of Gag and the production of viral particles [2,3,5,8,11,12].”
Background
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“Association with lipid raft-associated phosphatidylinositol- (4,5)-bisphosphate (PI(4,5)P2) induces a “myristyl-switch” whereby a subtle conformational change in MA exposes the myr moiety (Ono et al., 2004; Scarlata et al., 1998; Spearman et al., 1997; Tang et al., 2004; Zhou and Resh, 1996).”
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Background
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“1994), leading to the proposal that these positively charged residues might interact with negatively charged phospholipids on the inner leaflet of the lipid bilayer (Hermida-Matsumoto and Resh 1999; Zhou and Resh 1996).”
Molecular characterization of HIV-1 genome in fission yeast Schizosaccharomyces pombe
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“P17 Cytoplasm, membrane [52] Cytoplasm”
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“The residues of the matrix were identified as specific to the PI(4,5)P2 interactions [41,42].”
Background
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“Its MA domain is mainly responsible for membrane interaction and targeting to the plasma membrane (Ono et al., www.frontiersin.org May 2014 | Volume 5 | Article 220 | 3 2000), although MA alone seems to exhibit a lower affinity for membrane than Gag (Zhou and Resh, 1996).”
Background
Defect of Human Immunodeficiency Virus Type 2 Gag Assembly in Saccharomyces cerevisiae
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“Although it has been accepted that Gag oligomerization and membrane targeting are essentially independent events, recent studies have suggested that the membrane affinity of Gag may be promoted by Gag multimerization (43, 55).”
Background
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“Since it has long been known that the myristoyl is involved in binding of Gag to the PM [60], we thought it was important for this biophysical study to test the effect of the myristoyl group by studying MA31 in addition to MA31myr.”
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“The myristoyl moiety can be exposed or sequestered in the hydrophobic pocket of the mature MA (Figure 3a,b) by the so-called myristoyl-conformational switch [37,39,42,44,45], which controls the exposure of myristoyl group for insertion into the PM, thus contributing to the prevention of aberrant interactions with intr…”
Background
Dominant Negative Inhibition of Human Immunodeficiency Virus Particle Production by the Nonmyristoylated Form of Gag
Kawada, S., Goto, T., Haraguchi, H., Ono, A., & Morikawa, Y. (2008) · Journal of Virology · doi:10.1128/jvi.01953-07 · Cited by 18
“Previous studies have indicated that progressive C-terminal truncations of Gag that remove Gag-Gag interaction domains resulted in a decrease in the membrane affinity of Gag, suggesting that multimerization of Gag enhanced its membrane affinity (60, 72).”
Result
Conditions for Copackaging Rous Sarcoma Virus and Murine Leukemia Virus Gag Proteins during Retroviral Budding
Bennett, R., & Wills, J. (1999) · Journal of Virology · doi:10.1128/jvi.73.3.2045-2051.1999 · Cited by 20
“Individual N-terminal membrane-binding domains from Gag proteins are capable of directing heterologous proteins to the appropriate membrane (37, 44, 45), but the mechanism(s) by which this happens is not known.”
Background
Structural basis for targeting avian sarcoma virus Gag polyprotein to the plasma membrane for virus assembly
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Substitution of leucine 8 in the simian immunodeficiency virus matrix protein impairs particle formation without affecting N-myristylation of the Gag precursor.
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“Similar assays have been extensively used to define membrane associations of HIV-1 Gag (Bryant and Ratner, 1990; Park and Morrow, 1992; Yuan et al., 1993; Zhou and Resh, 1996).”
Method
Murine Leukemia Virus Gag Localizes to the Uropod of Migrating Primary Lymphocytes
Li, F., Sewald, X., Jin, J., Sherer, N. M., & Mothes, W. (2014) · Journal of Virology · doi:10.1128/jvi.01104-14 · Cited by 15
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Basic Residues in the Matrix Domain and Multimerization Target Murine Leukemia Virus Gag to the Virological Synapse
Li, F., Jin, J., Herrmann, C., & Mothes, W. (2013) · Journal of Virology · doi:10.1128/jvi.03263-12 · Cited by 18
IQGAP1 Negatively Regulates HIV-1 Gag Trafficking and Virion Production
Sabo, Y., Santos, K. D. L., & Goff, S. P. (2020) · Cell Reports · doi:10.1016/j.celrep.2020.03.002 · Cited by 16
“…and are co-translationally modified by the addition of N-terminal myristate (Göttlinger et al., 1989; Pal et al., 1990), which is required for their targeting to the host plasma membrane (Bouamr et al., 2003; Bryant and Ratner, 1990; Ono and Freed, 1999; Saad et al., 2007; Zhou and Resh, 1996).”
Cellular kinases incorporated into HIV-1 particles: passive or active passengers?
Giroud, C., Chazal, N., & Briant, L. (2011) · Retrovirology · doi:10.1186/1742-4690-8-71 · Cited by 16
Structural characterization of membrane-bound human immunodeficiency virus-1 Gag matrix with neutron reflectometry
Eells, R., Barros, M., Scott, K. M., Karageorgos, I. L., Heinrich, F., & Lösche, M. (2017) · Biointerphases · doi:10.1116/1.4983155 · Cited by 14
Elicitation of Immunity to HIV Type 1 Gag Is Determined by Gag Structure
Young, K. R., & Ross, T. M. (2006) · AIDS Research and Human Retroviruses · doi:10.1089/aid.2006.22.99 · Cited by 14
Opposing effects of the M368A point mutation and deletion of the SP1 region on membrane binding of human immunodeficiency virus type 1 Gag
Guo, X., & Liang, C. (2005) · Virology · doi:10.1016/j.virol.2005.03.004 · Cited by 14
“The M domain consists of a myristyl moiety that is covalently attached to a glycine that anchors Gag to the lipid bilayer as well as a group of basic amino acids that further stabilize Gag–membrane association through electrostatic interaction with the negatively charged phosphate groups (Gottlinger et al., 1989; Hill…”
BackgroundResult
The influence of myristoylation, liposome surface charge and nucleic acid interaction in the partition properties of HIV-1 Gag-N-terminal peptides to membranes
Socas, L. B. P., & Ambroggio, E. E. (2020) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2020.183421 · Cited by 12
Molecular Determinants in tRNA D-arm Required for Inhibition of HIV-1 Gag Membrane Binding
Sumner, C. A., Kotani, O., Liu, S., Musier‐Forsyth, K., Sato, H., & Ono, A. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167390 · Cited by 15
Biophysical characterization and crystal structure of the Feline Immunodeficiency Virus p15 matrix protein
Serrière, J., Robert, X., Perez, M., Gouet, P., & Guillon, C. (2013) · Retrovirology · doi:10.1186/1742-4690-10-64 · Cited by 13
“In the HIV model, the N-terminal myristoyl group of MA can adopt sequestered and exposed conformations [21] consistent with a myristoyl switch mechanism for regulating membrane binding [22-25].”
Background
Assembly of the HIV-1 core particle.
Kaplan, A. H. (2002) · PubMed · Cited by 13
The N-Terminal Matrix Domain of HIV-1 Gag Is Sufficient but Not Necessary for Viral Protein U-Mediated Enhancement of Particle Release through a Membrane-Targeting Mechanism
Deora, A., Spearman, P. W., & Ratner, L. (2000) · Virology · doi:10.1006/viro.1999.0094 · Cited by 13
Inhibition of viral assembly in murine cells by HIV-1 matrix.
Hübner, W., & Chen, B. K. (2006) · Virology · doi:10.1016/j.virol.2006.04.024 · Cited by 18
“Deletion of the globular head of MA, while maintaining a small myristoyl anchor, increases the intrinsic membrane affinity of Gag (Lindwasser and Resh, 2001; Spearman et al., 1997; Zhou and Resh, 1996) and in some circumstances can enhance rather than inhibit the production of virus like particles (Reil et al.”
Background
Interaction of Mason-Pfizer monkey virus matrix protein with plasma membrane
Prchal, J., Kroupa, T., Ruml, T., & Hrabal, R. (2014) · Frontiers in Microbiology · doi:10.3389/fmicb.2013.00423 · Cited by 12
“In retroviruses, the mechanism was well described for the interaction of HIV-1 MA with PM (Zhou and Resh, 1996; Tang et al., 2004; Saad et al., 2006).”
Background
Differential S-acylation of Enveloped Viruses
Kordyukova, L. V., Serebryakova, M. V., Khrustalev, V. V., & Veit, M. (2019) · Protein and Peptide Letters · doi:10.2174/0929866526666190603082521 · Cited by 12
Interleukin 2-inducible T cell kinase (ITK) facilitates efficient egress of HIV-1 by coordinating Gag distribution and actin organization
Lester, G. M. S., Akiyama, H., Evans, E. K., Singh, J., Gummuluru, S., & Henderson, A. J. (2012) · Virology · doi:10.1016/j.virol.2012.11.015 · Cited by 11
“Deleting or mutating the highly basic domain alters the cellular distributions of Gag away from the plasma membrane and into intracellular compartments such as the endoplasmic reticulum, late endosomes or MVBs (Facke et al., 1993; Ono et al., 2004; Ono and Freed, 2004; Zhou and Resh, 1996).”
Background
Downregulation of human immunodeficiency virus type 1 Gag expression by a gp41 cytoplasmic domain fusion protein
Chan, W.-E., & Chen, S. S.-L. (2006) · Virology · doi:10.1016/j.virol.2006.01.010 · Cited by 11
HIV-1 Gag Trafficking
Joshi, A., & Freed, E. O. (2007) · Future HIV Therapy · doi:10.2217/17469600.1.4.427 · Cited by 11
Integrase inhibitors: current protagonists in antiretroviral therapy
Loaiza, J. D., Chvatal‐Medina, M., Hernández, J. C., & Rugeles, M. T. (2023) · Immunotherapy · doi:10.2217/imt-2023-0011 · Cited by 10
The matrix domain of the Gag protein from avian sarcoma virus contains a PI(4,5)P2-binding site that targets Gag to the cell periphery
Watanabe, S. M., Medina, G. N., Eastep, G. N., Ghanam, R. H., Vlach, J., Saad, J. S., & Carter, C. A. (2018) · Journal of Biological Chemistry · doi:10.1074/jbc.ra118.003947 · Cited by 10
“Myr exposure is known to promote membrane binding (6, 7).”
Background
Maturation of the Gag core decreases the stability of retroviral lipid membranes
Davidoff, C., Payne, R. J., Willis, S. H., Doranz, B. J., & Rucker, J. B. (2012) · Virology · doi:10.1016/j.virol.2012.08.023 · Cited by 10
“By directing the cellular location of budding, viral structural proteins, such as the matrix component of the retrovirus Gag polyprotein, help to determine the lipid composition of the viral membrane (Ono et al., 2000; Spearman et al., 1997; Zhou and Resh, 1996).”
Background
Specificity of Plasma Membrane Targeting by the Rous Sarcoma Virus Gag Protein
Scheifele, L. Z., Rhoads, J. D., & Parent, L. J. (2002) · Journal of Virology · doi:10.1128/jvi.77.1.470-480.2003 · Cited by 10
“This hypothesis is supported by biochemical data indicating that the membrane association of MA is much weaker than Gag (19, 32, 47, 59) and that MA and Gag bind to the membrane in distinct conformations (9, 43).”
Background
Binding to PI(4,5)P2 is indispensable for secretion of B-cell clonogenic HIV-1 matrix protein p17 variants
Bugatti, A., Caccuri, F., Filippini, F., Ravelli, C., & Caruso, A. (2021) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2021.100934 · Cited by 9
“When reported, Jurkat cells were conucleofected with the 5ptaseIV expression plasmid pcDNA4TO/Myc5ptaseIV66 or with the mutant expression plasmid pcDNA4TO/Myc Δ15ptaseIV (36, 50).”
Method
Structural Insights into the Mechanism of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly
Herrmann, D., Zhou, L. W., Hanson, H. M., Willkomm, N. A., Mansky, L. M., & Saad, J. S. (2021) · Journal of Molecular Biology · doi:10.1016/j.jmb.2021.167161 · Cited by 9
Improvement of lentiviral vector-mediated gene transduction by genetic engineering of the structural protein Pr55Gag
Aoki, T., Shimizu, S., Urano, E., Futahashi, Y., Hamatake, M., Tamamura, H., Terashima, K., Murakami, T., Yamamoto, N., & Komano, J. A. (2010) · Gene Therapy · doi:10.1038/gt.2010.61 · Cited by 9
Interaction of HIV-1 Gag and Membranes in a Cell-Free System
Yang, L., & Ratner, L. (2002) · Virology · doi:10.1006/viro.2002.1532 · Cited by 9
Visualization of Retroviral Gag-Genomic RNA Cellular Interactions Leading to Genome Encapsidation and Viral Assembly: An Overview
Bernacchi, S. (2022) · Viruses · doi:10.3390/v14020324 · Cited by 8
“Zhou and Resh proposed that specific Gag binding to the PM is regulated by a mechanism named “myristyl switch [31], and several other groups analyzed the molecular mechanisms promoting the exposure of the myristyl group for its insertion into the PM [32–35].”
Background
Investigation of HIV-1 Gag binding with RNAs and lipids using Atomic Force Microscopy
Chen, S., Xu, J. C., Liu, M., Rao, A. L. N., Zandi, R., Gill, S. S., & Mohideen, U. (2020) · PLoS ONE · doi:10.1371/journal.pone.0228036 · Cited by 10
“This then triggers the exposure of the myristylated group for insertion into the lipid bilayer membrane [37-40].”
Background
A facile quantitative assay for viral particle genesis reveals cooperativity in virion assembly and saturation of an antiviral protein
Yadav, S. S., Wilson, S. J., & Bieniasz, P. D. (2012) · Virology · doi:10.1016/j.virol.2012.04.008 · Cited by 8
“In Gag monomers, the N-terminal myristoyl group exhibits a propensity to be occluded within a pocket in the MA domain, while Gag oligomerization induces myristoyl group exposure (Tang et al., 2004; Zhou and Resh, 1996).”
Background
Myristoylation and Oligonucleotide Interaction Modulate Peptide and Protein Surface Properties: The Case of the HIV-1 Matrix Domain
Socas, L. B. P., & Ambroggio, E. E. (2018) · Langmuir · doi:10.1021/acs.langmuir.8b01005 · Cited by 7
Cross-Reactivity of Anti-HIV-1-p17-Derivative Peptide (P30–52) Antibody to Env V3 Peptide
Ota, A., Tanaka-Taya, K., & Ueda, S. (1999) · Hybridoma · doi:10.1089/hyb.1999.18.149 · Cited by 6
Molecular Determinants of Human T-cell Leukemia Virus Type 1 Gag Targeting to the Plasma Membrane for Assembly
Herrmann, D., Hanson, H. M., Zhou, L. W., Addabbo, R. M., Willkomm, N. A., Angert, I., Mueller, J. D., Mansky, L. M., & Saad, J. S. (2022) · Journal of Molecular Biology · doi:10.1016/j.jmb.2022.167609 · Cited by 5
HIV-1 Gag specificity for PIP2 is regulated by macromolecular electric properties of both protein and membrane local environments
Socas, L. B. P., & Ambroggio, E. E. (2023) · Biochimica et Biophysica Acta (BBA) - Biomembranes · doi:10.1016/j.bbamem.2023.184157 · Cited by 6
Beyond reverse transcription: molecular mechanisms and emerging paradigms in retroviral replication
Jehad, M. A., Ali, L. M., Pillai, V. N., Prabhu, S. G., Mustafa, F., & Rizvi, T. A. (2026) · FEMS Microbiology Reviews · doi:10.1093/femsre/fuaf066 · Cited by 5
“…by the myristol switch mechanism, during which the myristol group is exposed in the context of full-length Gag, but gets sequestered in the purified MA protein (Zhou and Resh 1996 , Spearman et al. 1997 , Hermida-Matsumoto and Resh 1999 , Ono and Freed 1999 , Paillart and Göttlinger 1999 ).”
HIV‐1 matrix domain removal ameliorates virus assembly and processing defects incurred by positive nucleocapsid charge elimination
Ko, L.-J., Yu, F.-H., Huang, K.-J., & Wang, C.-T. (2015) · FEBS Open Bio · doi:10.1016/j.fob.2015.04.003 · Cited by 4
Sensitive Detection of Protein Binding to the Plasma Membrane with Dual-Color Z-Scan Fluorescence
Angert, I., Karuka, S. R., Hennen, J., Chen, Y., Albanesi, J. P., Mansky, L. M., & Mueller, J. D. (2019) · Biophysical Journal · doi:10.1016/j.bpj.2019.12.002 · Cited by 4
Introduction to Retroviruses
Goff, S. P. (2004) · Elsevier eBooks · doi:10.1016/b978-012764051-8/50006-8 · Cited by 4
Membrane Interactions of the Mason-Pfizer Monkey Virus Matrix Protein and Its Budding Deficient Mutants
Kroupa, T., Langerová, H., Doležal, M., Prchal, J., Spiwok, V., Hunter, E., Rumlová, M., Hrabal, R., & Ruml, T. (2016) · Journal of Molecular Biology · doi:10.1016/j.jmb.2016.10.010 · Cited by 5
The Role of v-Fgr Myristoylation and the Gag Domain in Membrane Binding and Cellular Transformation
Baker, S. J., Cosenza, S. C., & Reddy, E. P. (1998) · Virology · doi:10.1006/viro.1998.9323 · Cited by 4
“For example, other groups (Platt and Haffar, 1994; Zhou and Resh, 1996) have determined that both N- and C-terminal sequences in the HIV Type 1 Pr55 protein, in conjunction with the myristate moiety, are required to target gag precursor proteins to the plasma membrane.”
BackgroundInfluential
Hrs inhibits citron kinase-mediated HIV-1 budding via its FYVE domain
Ding, J., Su, L., & Gao, G. (2011) · Protein & Cell · doi:10.1007/s13238-011-1053-y · Cited by 3
“The Nterminus of the MA domain contains a series of basic amino acids, which are required for the interaction with acidic phospholipids, and a myristyl group (Paillart and Gottlinger, 1999), which is believed to facilitate Gag targeting to membranes (Zhou and Resh, 1996; Spearman et al., 1997; Tang et al., 2004).”
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Fluorescence lifetime imaging applied to multiwell plate FRET assays for high content analysis
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Role of Host Factors in the Subcellular Trafficking of Gag Proteins and Genomic RNA Leading to Virion Assembly
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Membrane Relocation but Not Tight Binding of Human Immunodeficiency Virus Type 1 Gag Particles Myristoylated in Escherichia coli
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The dominant-negative action of a fusion protein containing the cytoplasmic domain of human immunodeficiency virus type 1 transmembrane protein gp41 in virus replication
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Effects of mutations in an HIV‐1 gag gene containing a 107‐codon tandem repeat in the matrix region on assembly and processing of the protein product
Liao, W., Chiu, H.-C., & Wang, C.-T. (2004) · Journal of Medical Virology · doi:10.1002/jmv.20209 · Cited by 2
Anti-P30-52 Monoclonal Antibody Cross-Reacted to Env V3 and Inhibited the Viral Multiplication of HIV-1-Infected MT-4 Cells
Ota, A., BAUTISTA, A. N., YADAV, M. L., & Ueda, S. (1999) · Hybridoma · doi:10.1089/hyb.1999.18.139 · Cited by 1
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Authors: Zhou, W., & Resh, M. D.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
ORCID: Resh, M D
Venue: Journal of Virology
Publisher: American Society for Microbiology
Published: 1996-12
Volume: 70
Issue: 12
Pages: 8540-8548
ISSN: 0022-538X (ISSN-L)
1098-5514
DOI: 10.1128/jvi.70.12.8540-8548.1996
PMC: PMC190946
OpenAlex: W2102965972
Cited by: 226
References: 47
Citations by year: 2026: 1 · 2025: 2 · 2023: 3 · 2022: 6 · 2021: 4 · 2020: 5 · 2019: 3 · 2018: 9 · 2017: 3 · 2016: 4 · 2015: 6 · 2014: 10 · 2013: 10 · 2012: 13
FWCI: 3.01
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: journals.asm.org/non-commercial-tdm-license (tdm)
Locations: Journal of Virology (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Cancer Institute (CA 72309, R01CA072309)
Topics: Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Lipid Membrane Structure and Behavior
Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
Keywords: HIV-1, Pr55gag, membrane binding, myristate, myristoylation, plasma membrane targeting, viral assembly, nuclear targeting, protein conformational change, liposome binding, subcellular localization
MeSH terms: Animals, Epitopes, Cell Membrane, Humans, Myristic Acids, Protein Precursors, Viral Proteins, Signal Transduction, HIV Antigens, HIV-1, Gene Products, gag, Sequence Deletion, COS Cells, Myristic Acid, gag Gene Products, Human Immunodeficiency Virus

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Differential membrane binding of the human immunodeficiency virus type 1 matrix protein

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