A single amino acid substitution within the matrix protein of a type D retrovirus converts its morphogenesis to that of a type C retrovirus

Rhee, Sehun; Hunter, Eric

doi:10.1016/0092-8674(90)90289-q

Cited by 159 publications

(177 citation statements)

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“…Perhaps the most dramatic effect on morphogenesis was demonstrated by the replacement of arginine 55 of the M-PMV MA protein with a large hydrophobic amino acid residue (i.e., tryptophan or phenylalanine), which resulted in translocation of virus particle assembly to the plasma membrane (15,16). In this respect, the virus behaves similarly to HIV-1 and other C-type retroviruses.…”

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confidence: 79%

D-retrovirus morphogenetic switch driven by the targeting signal accessibility to Tctex-1 of dynein

Vlach

Lipov

Rumlová

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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Despite extensive data demonstrating that immature retroviral particle assembly can take place either at the plasma membrane or at a distinct location within the cytoplasm, targeting of viral precursor proteins to either assembly site still remains poorly understood. Biochemical data presented here suggest that Tctex-1, a light chain of the molecular motor dynein, is involved in the intracellular targeting of Mason-Pfizer monkey virus (M-PMV) polyproteins to the cytoplasmic assembly site. Comparison of the three-dimensional structures of M-PMV wild-type matrix protein (wt MA) with a single amino acid mutant (R55F), which redirects assembly from a cytoplasmic site to the plasma membrane, revealed different mutual orientations of their C-and N-terminal domains. This conformational change buries a putative intracellular targeting motif located between both domains in the hydrophobic pocket of the MA molecule, thereby preventing the interaction with cellular transport mechanisms.capsid assembly ͉ dynein motor ͉ matrix protein structure ͉ retrovirus ͉ transport G ag polyproteins are major structural subunits of immature retroviral capsids and contain the determinants that mediate interactions with viral genomic RNA as well as particle assembly. The molecular mechanisms that control the accumulation of Gag molecules at the sites of assembly vary among retroviruses. Based on the assembly site, retroviruses have been shown to follow two major morphogenic pathways (1). While alpharetroviruses, gammaretroviruses, and lentiviruses (C-type retroviruses) assemble immature capsids at the inner side of the plasma membrane, the capsids of betaretroviruses (B/D-type) are formed in the cytoplasm. It has been shown that MasonPfizer monkey virus (M-PMV), which is the prototype of the D-type retroviruses, assembles at the pericentriolar region of an infected cell (2). Numerous studies have demonstrated that the matrix protein (MA), located at the N terminus of the Gag polyprotein, is responsible for targeting the polyprotein precursors to the site of assembly and for mediating transport of immature retroviral particles to the plasma membrane where budding occurs (3). A subtle difference in the regulation of the transport process has been suggested, as the results from several laboratories indicate that the destination of polyprotein precursors can be altered by mutations within MA. Amino acid substitutions in several domains of HIV-1 MA dramatically reduced the efficiency of particle production and redirected the majority of them to cytoplasmic vacuoles (4). Similarly, a substitution of basic for acidic residues in helix A of HIV-1 MA caused relocation of virus assembly to intracellular locations and produced normally budded noninfectious virions (5). Mutation of the N-terminal polybasic region of Moloney murine leukemia virus (Mo-MuLV) MA redirected virus assembly to the cytoplasm, suggesting a role of tryptophan residues in the intracellular transport (6).The N terminus of MA from most retroviruses, including M-PMV, is myristoylat...

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confidence: 79%

D-retrovirus morphogenetic switch driven by the targeting signal accessibility to Tctex-1 of dynein

Vlach

Lipov

Rumlová

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

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“…The assembly of curved and closed shells of Gag protein in the cytoplasm of host ceils indicates that association with a membrane is not essential for the curvature of Gag. The formation of Gag particles and other assemblies of Gag protein presumably occurs wherever Gag molecules accumulate at a concentration sufficient for self-assembly, as has been suggested for other retroviruses (Rhee & Hunter, 1990). Curvature may be an intrinsic property of the protein itself and may possibly be explained by the shape of the Gag molecule and/or the arrangement of bonds that link Gag molecules together.…”

Section: Discussionmentioning

confidence: 99%

Comparative Morphology of Gag Protein Structures Produced by Mutants of the gag Gene of Human Immunodeficiency Virus Type 1

Hockley

Nermut

Grief

et al. 1994

Journal of General Virology

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“…Eighty percent of pulse-labeled Gag polyprotein was incorporated into immature capsids for wild type and A18V, a mutant that accumulates capsids in the cytoplasm (25). R55W, a mutant that assembles capsids at the plasma membrane (27), demonstrated only 50% Gag polyprotein was incorporated into capsids after the 30-min chase. In contrast, in cells expressing the major homology domain mutant, L163H, which does not assemble immature capsids (28,36), less than 20% of Gag was pelletable.…”

Section: Construction Of M-pmv Matrix Mutantsmentioning

confidence: 99%

“…Mason-Pfizer monkey virus (M-PMV), a betaretrovirus, assembles an immature protein shell (capsid) from its Gag polyproteins in a pericentriolar region of the cytoplasm prior to plasma membrane transport and viral budding (14,27,32). In contrast, viruses such as human immunodeficiency virus (HIV) assemble an immature capsid as they bud at the plasma membrane (14).…”

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confidence: 99%

“…This means that instead of simultaneously extruding the membrane as they assemble, assembled betaretrovirus capsids must interact with the plasma membrane in a way that stimulates wrapping of the spherical structure with the lipid bilayer. The matrix (MA) domain of the M-PMV Gag polyprotein plays a critical role in this process (25), as well as in directing translating polysomes to the intracellular assembly site (32) and subsequent transport to the plasma membrane (8,25,27,32). MA is cotranslationally modified with myristic acid, a 14-carbon saturated fatty acid, and while myristylation of this domain is dispensable for capsid assembly, it is required for transport and release of capsids (26,29).…”

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An Early Stage of Mason-Pfizer Monkey Virus Budding Is Regulated by the Hydrophobicity of the Gag Matrix Domain Core

Stansell

Tytler

Walter

et al. 2004

J Virol

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Intracellular capsid transport and release of Mason-Pfizer monkey virus are dependent on myristylation of the Gag matrix domain (MA). A myristylated MA mutant, in which Thr41 and Thr78 are replaced with isoleucines, assembles capsids that are transported to the plasma membrane but are blocked in an early budding step. Since the nuclear magnetic resonance structure of MA showed that these Thr residues point into the hydrophobic core of the protein, it was hypothesized that the T41I/T78I mutant was defective in release of myristic acid from the more hydrophobic core. In order to further investigate whether an increase in the hydrophobicity of the MA core modulates capsid-membrane interactions and viral budding, three tyrosine residues (11, 28, and 67), oriented toward the MA core, were replaced individually or in a pair-wise combination with the more hydrophobic phenylalanine residue(s). As a control, Tyr82, oriented toward the outer surface of MA, was also replaced with phenylalanine. These Tyr-to-Phe substitutions did not alter capsid assembly compared to wild type in a capsid assembly assay. Pulse-chase, immunofluorescence, and electron microscopy studies demonstrated that single substitutions of Tyr11, Tyr28, and Tyr67 recapitulated the T41I/T78I mutant phenotype of decreased budding kinetics and accumulation of capsids at the plasma membrane. MA double mutants with a combination of these Tyr substitutions exhibited a phenotype that was even more defective in budding. In contrast, MA mutants with Tyr82 replaced by Phe resulted in a transportdefective phenotype. These results strongly support the hypothesis that myristic acid is sequestered inside MA prior to capsid-membrane interactions.

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A single amino acid substitution within the matrix protein of a type D retrovirus converts its morphogenesis to that of a type C retrovirus

Cited by 159 publications

References 50 publications

D-retrovirus morphogenetic switch driven by the targeting signal accessibility to Tctex-1 of dynein

D-retrovirus morphogenetic switch driven by the targeting signal accessibility to Tctex-1 of dynein

Comparative Morphology of Gag Protein Structures Produced by Mutants of the gag Gene of Human Immunodeficiency Virus Type 1

An Early Stage of Mason-Pfizer Monkey Virus Budding Is Regulated by the Hydrophobicity of the Gag Matrix Domain Core

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