Crystal structures of the trimeric human immunodeficiency virus type 1 matrix protein: implications for membrane association and assembly.

Hill, Christopher P.; Worthylake, David K.; Bancroft, Daniel P.; Christensen, Allyson M.; Sundquist, Wesley I.

doi:10.1073/pnas.93.7.3099

Cited by 450 publications

(558 citation statements)

References 68 publications

(28 reference statements)

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“…3A). This finding, although in line with known structural features of recombinant HIV-1 p17 characterized by NMR spectroscopy and x-ray crystallography (28,29), also supports the conclusion that synthetic p17 is correctly folded. Further evidence for the correct folding of synthetic p17 comes from studies of GuHCl-induced denaturation (Fig.…”

Section: Myristoylation Of P17 Results In Little Structural Change Ansupporting

confidence: 72%

“…Recently, the solution structure of a 283-residue N-terminal fragment of the immature HIV-1 Gag polyprotein comprising both the p17 domain and the downstream capsid protein has been determined (57). The p17 domain in the immature Gag polyprotein assumed an essentially identical structure to that observed for the cleaved form determined by x-ray crystallography and NMR spectroscopy (28,29), suggesting that proteolysis did not induce structural changes in p17. The proteins used for structural determination were nonmyristoylated, leaving room for uncertainty as to whether proteolysis leads to structural changes in myristoylated proteins.…”

Section: Myristoylation Of P17 Results In Little Structural Change Anmentioning

confidence: 99%

“…The question of how proteolytic processing of the Gag polyprotein during viral maturation induces a significant structural change in p17, and thus sequestration of the myristoyl moiety, remains unanswered. Although both NMR and crystal structures of recombinant nonmyristoylated p17 have been determined (25)(26)(27)(28)(29), these studies shed little light on the structural basis of the myristoyl switch hypothesis. Comparative studies of both myristoylated and nonmyristoylated p17 are needed to better understand the molecular mechanism by which it functions in the early and late stages of the HIV-1 life cycle.…”

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confidence: 99%

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Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation

Alexandratos

Ericksen

et al. 2004

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

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The HIV-1 matrix protein p17, excised proteolytically from the N terminus of the Gag polyprotein, forms a protective shell attached to the inner surface of the plasma membrane of the virus. During the late stages of the HIV-1 replication cycle, the N-terminally myristoylated p17 domain targets the Gag polyprotein to the host-cell membrane for particle assembly. In the early stages of HIV-1 replication, however, some p17 molecules dissociate from the viral membrane to direct the preintegration complex to the host-cell nucleus. These two opposing targeting functions of p17 require that the protein be capable of reversible membrane interaction. It is postulated that a significant structural change in p17 triggered by proteolytic cleavage of the Gag polyprotein sequesters the N-terminal myristoyl group, resulting in a weaker membrane binding by the matrix protein than the Gag precursor. To test this ''myristoyl switch'' hypothesis, we obtained highly purified synthetic HIV-1 p17 of 131 amino acid residues and its N-myristoylated form in large quantity. Both forms of p17 were characterized by circular dichroism spectroscopy, protein chemical denaturation, and analytical centrifugal sedimentation. Our results indicate that although N-myristoylation causes no spectroscopically discernible conformational change in p17, it stabilizes the protein by 1 kcal͞ mol and promotes protein trimerization in solution. These findings support the premise that the myristoyl switch in p17 is triggered not by a structural change associated with proteolysis, but rather by the destabilization of oligomeric structures of membranebound p17 in the absence of downstream Gag subdomains.

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Section: Myristoylation Of P17 Results In Little Structural Change Ansupporting

confidence: 72%

Section: Myristoylation Of P17 Results In Little Structural Change Anmentioning

confidence: 99%

mentioning

confidence: 99%

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Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation

Alexandratos

Ericksen

et al. 2004

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

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“…However, the blocking of Env incorporation can in turn be overcome by deletions in the long cytoplasmic tail of Env (13,14,17,32). These results support the notion that the long cytoplasmic tail of the trimeric Env has to fit the cage hole present in the lattice-like MA trimeric structure during virus assembly (20,38). Nevertheless, whether the reduced Env incorporation observed with these mutants correlates with impaired Env-Gag interaction in cells was not addressed in those studies.…”

supporting

confidence: 74%

Effect of Extension of the Cytoplasmic Domain of Human Immunodeficiency Type 1 Virus Transmembrane Protein gp41 on Virus Replication

Chan

Wang

Lin

et al. 2004

J Virol

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The biological significance of the presence of a long cytoplasmic domain in the envelope (Env) transmembrane protein gp41 of human immunodeficiency virus type 1 (HIV-1) is still not fully understood. Here we examined the effects of cytoplasmic tail elongation on virus replication and characterized the role of the C-terminal cytoplasmic tail in interactions with the Gag protein. Extensions with six and nine His residues but not with fewer than six His residues were found to severely inhibit virus replication through decreased Env electrophoretic mobility and reduced Env incorporation compared to the wild-type virus. These two mutants also exhibited distinct N glycosylation and reduced cell surface expression. An extension of six other residues had no deleterious effect on infectivity, even though some mutants showed reduced Env incorporation into the virus and/or decreased cell surface expression. We further show that these elongated cytoplasmic tails in a format of the glutathione S-transferase fusion protein still interacted effectively with the Gag protein. In addition, the immediate C terminus of the cytoplasmic tail was not directly involved in interactions with Gag, but the region containing the last 13 to 43 residues from the C terminus was critical for Env-Gag interactions. Taken together, our results demonstrate that HIV-1 Env can tolerate extension at its C terminus to a certain degree without loss of virus infectivity and Env-Gag interactions. However, extended elongation in the cytoplasmic tail may impair virus infectivity, Env cell surface expression, and Env incorporation into the virus.

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“…The ligands reported here could be used to characterize the molecular interactions between matrix and RNA, since at this time the nature of those interactions is not known. In the structures of the HIV-1 (41)(42)(43) and SIV matrix (44) proteins there is a patch of basic amino acids near the amino terminus that is located on one face of the protein. This region serves as the nuclear localization signal of matrix (8).…”

Section: Discussionmentioning

confidence: 99%

In vitro selection of RNAs that bind to the human immunodeficiency virus type-1 gag polyprotein

Lochrie

Waugh²,

Pratt³

et al. 1997

Nucleic Acids Research

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Crystal structures of the trimeric human immunodeficiency virus type 1 matrix protein: implications for membrane association and assembly.

Cited by 450 publications

References 68 publications

Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation

Total chemical synthesis of N-myristoylated HIV-1 matrix protein p17: Structural and mechanistic implications of p17 myristoylation

Effect of Extension of the Cytoplasmic Domain of Human Immunodeficiency Type 1 Virus Transmembrane Protein gp41 on Virus Replication

In vitro selection of RNAs that bind to the human immunodeficiency virus type-1 gag polyprotein

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