Relationships between plasma membrane microdomains and HIV‐1 assembly

Ono, Akira

doi:10.1042/bc20090165

Cited by 100 publications

(104 citation statements)

References 185 publications

(296 reference statements)

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“…The N-terminal region of MA (residues 2-47) is critical for various MA functions. Among these functions is its role in mediating Gag-membrane interactions and regulation of the myr switch mechanism (4,5,22,23,27,57,58,73,81,82). Helix I of MA is implicated in Gag binding to several cellular constituents including the AP-3 complex (11) and TIP47 (29).…”

Section: Discussionmentioning

confidence: 99%

“…HIV-1 Gag targeting to the plasma membrane (PM) 2 is critical for proper and efficient assembly to produce progeny virions (1,(3)(4)(5)(6)(7)(8)(9). During virus maturation, Gag is cleaved into myristoylated matrix (myr(ϩ)MA), capsid, and nucleocapsid proteins, inducing major morphological reorganization of the virus (1,2,4,5,10). In many cell types, HIV-1 Gag budding and assembly has been shown to occur predominantly on the PM (4 -9, 11-18).…”

mentioning

confidence: 99%

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Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Ghanam

Fernandez

Fledderman

et al. 2010

Journal of Biological Chemistry

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Steady progress has been made in defining both the viral and cellular determinants of retroviral assembly and release. Although it is widely accepted that targeting of the Gag polypeptide to the plasma membrane is critical for proper assembly of HIV-1, the intracellular interactions and trafficking of Gag to its assembly sites in the infected cell are poorly understood. HIV-1 Gag was shown to interact and co-localize with calmodulin (CaM), a ubiquitous and highly conserved Ca 2؉ -binding protein expressed in all eukaryotic cells, and is implicated in a variety of cellular functions. Binding of HIV-1 Gag to CaM is dependent on calcium and is mediated by the N-terminally myristoylated matrix (myr(؉)MA) domain. Herein, we demonstrate that CaM binds to myr(؉)MA with a dissociation constant (K d ) of ϳ2 M and 1:1 stoichiometry. Strikingly, our data revealed that CaM binding to MA induces the extrusion of the myr group. However, in contrast to all known examples of CaM-binding myristoylated proteins, our data show that the myr group is exposed to solvent and not involved in CaM binding. The interactions between CaM and myr(؉)MA are endothermic and entropically driven, suggesting that hydrophobic contacts are critical for binding. As revealed by NMR data, both CaM and MA appear to engage substantial regions and/or undergo significant conformational changes upon binding. We believe that our findings will provide new insights on how Gag may interact with CaM during the HIV replication cycle.Gag is the major structural protein encoded by HIV-1 and contains all of the viral elements required to drive virus assembly (1-3). HIV-1 Gag targeting to the plasma membrane (PM) 2 is critical for proper and efficient assembly to produce progeny virions (1, 3-9). During virus maturation, Gag is cleaved into myristoylated matrix (myr(ϩ)MA), capsid, and nucleocapsid proteins, inducing major morphological reorganization of the virus (1, 2, 4, 5, 10). In many cell types, HIV-1 Gag budding and assembly has been shown to occur predominantly on the PM (4 -9, 11-18). Gag binding to the PM is mediated by the MA domain and enhanced by multimerization. Proper assembly and efficient binding of Gag to the PM requires a myristyl (myr) group as a membrane anchor and a cluster of basic residues localized within the N-terminal domain to facilitate interactions with acidic phospholipids (1,2,19,20).Steady progress has been made in defining both the viral and cellular determinants of HIV-1 assembly and release (6). However, the trafficking pathway used by Gag to reach assembly sites in the infected cell is poorly understood. Studies by Freed, Ono, and co-workers (21-23) demonstrated that the ultimate localization of HIV-1 Gag at virus assembly sites is dependent on phosphatidylinositol-(4,5)-bisphosphate (PI(4,5)P 2 ), a cellular factor localized at the inner leaflet of the PM (24 -26). Our structural studies revealed that PI(4,5)P 2 binds directly to HIV-1 MA, inducing a conformational change that triggers myr exposure (27). In addition to PI(4,5)P 2 ...

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

Binding of Calmodulin to the HIV-1 Matrix Protein Triggers Myristate Exposure

Ghanam

Fernandez

Fledderman

et al. 2010

Journal of Biological Chemistry

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“…CD40 has a TM motif known to target the protein to lipid rafts, whereas the TM region of the raft protein CD45 is not involved in lipid raft targeting (28). Finally, the TM region of TfR was chosen because TfR is a well studied non-raft-associated protein (40). An alignment of the C-terminal residues of BST-2 WT, BST-2-CD40 (TM40), BST-2-CD45 (TM45), and BST-2-TfR (TMTfR) downstream of residue 150 is shown in We tested the ability of the TM40, TM45, and TfR chimeras to inhibit virus particle release.…”

Section: C-terminal Gpi Anchor In Bst-2 Can Bementioning

confidence: 99%

C-terminal Hydrophobic Region in Human Bone Marrow Stromal Cell Antigen 2 (BST-2)/Tetherin Protein Functions as Second Transmembrane Motif

Andrew

Kao

Strebel

2011

Journal of Biological Chemistry

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Background: BST-2/tetherin inhibits virus release by tethering virions to the cell surface. Results: The putative GPI anchor signal of BST can function as a TM region and can be replaced by heterologous TM segments. Conclusion: BST-2 contains a second TM region instead of a GPI anchor. Significance: Understanding the molecular structure of BST-2 is crucial to understanding how the protein inhibits detachment of many enveloped viruses.

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“…Given that incorporation of Huwe1 into HIV-1 virions was not detected, one possibility would be that Huwe1 blocks the proper intracellular localization of the Gag-Pol precursor. It has been well demonstrated that during HIV-1 particle assembly, viral structural proteins, including Gag-Pol, are taken up by the detergent-resistant membrane (DRM) fraction, the so called lipid raft, which is characterized by its insolubility against non-ionic detergents such as NP-40 (Halwani et al, 2003;Ono, 2010). In contrast, Huwe1 was distributed in a NP-40-soluble (non-DRM) fraction .…”

Section: Cellular Interactors Affecting On Postintegration Stepsmentioning

confidence: 91%