An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations.

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Research Abstract Details 

Research Abstract Table of Contents

Jump to the:

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Abstract Text:

Emily J Platt,James P Durnin,Ujwal Shinde,David Kabat,Emily J Platt,James P Durnin,Ujwal Shinde,David Kabat,

Binding of the human immunodeficiency virus (HIV-1) envelope glycoprotein gp120 to the CCR5 co-receptor reduces constraints on the metastable transmembrane subunit gp41, thereby enabling gp41 refolding, fusion of viral and cellular membranes, and infection. We previously isolated adapted HIV-1(JRCSF) variants that more efficiently use mutant CCR5s, including CCR5(Delta18) lacking the important tyrosine sulfate-containing amino terminus. Effects of mutant CCR5 concentrations on HIV-1 infectivities were highly cooperative, implying that several may be required. However, because wild-type CCR5 efficiently mediates infections at trace concentrations that were difficult to measure accurately, analyses of its cooperativity were not feasible. New HIV-1(JRCSF) variants efficiently use CCR5(HHMH), a chimera containing murine extracellular loop 2. The adapted virus induces large syncytia in cells containing either wild-type or mutant CCR5s and has multiple gp120 mutations that occurred independently in CCR5(Delta18)-adapted virus. Accordingly, these variants interchangeably use CCR5(HHMH) or CCR5(Delta18). Additional analyses strongly support a novel energetic model for allosteric proteins, implying that the adaptive mutations reduce quaternary constraints holding gp41, thus lowering the activation energy barrier for membrane fusion without affecting bonds to specific CCR5 sites. In accordance with this mechanism, highly adapted HIV-1s require only one associated CCR5(HHMH), whereas poorly adapted viruses require several. However, because they are allosteric ensembles, complexes with additional co-receptors fuse more rapidly and efficiently than minimal ones. Similarly, wild-type HIV-1(JRCSF) is highly adapted to wild-type CCR5 and minimally requires one. The adaptive mutations cause resistances to diverse entry inhibitors and cluster appropriately in the gp120 trimer interface overlying gp41. We conclude that membrane fusion complexes are allosteric machines with an ensemble of compositions, and that HIV-1 adapts to entry limitations by gp120 mutations that reduce its allosteric hold on gp41. These results provide an important foundation for understanding the mechanisms that control membrane fusion and HIV-1's facile adaptability.

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Publishing Authors By Initials

EJ Platt,JP Durnin,U Shinde,D Kabat,EJ Platt,JP Durnin,U Shinde,D Kabat,

For similar abstracts research abstracts see: abstracts research

PUBMED ID PMID:

MEDLINE DATE:

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Journal Published:

PUBLICATION TYPE: Research Support, N.I.H., Extr

Journal: Journal of molecular biology

VOLUME: 374

Page Numbers: 64-79

Journal Abbreviation: J. Mol. Biol.

ISSN: 1089-8638

DAY: 12

MONTH: 09

YEAR: 2007

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Information

Number of References:

LANGUAGE: eng

NlmUniqueID: 2985088

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Keywords Mesh Terms:

KEYWORDS:

MESH TERMS:

Chemical & Substance for Abstract: An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations. Information

Substance Name:

Registry Number:

Grant and Affiliation Information for An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations.

AFFILIATION: Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, OR 97239, USA.

Country: England

AGENCY: United States NCI

GRANT: CA67358

ACRONYM: CA

MEDLINETA: J Mol Biol

REFSOURCE:

DATABASENAME:

ACCESSION NUMBER:

Number Hits: 0

An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations Related Publications

• A quantitative study of passive anaphylaxis in the guinea pig; the latent period in passive anaphylaxis in its relation to the dose of rabbit antiovalbumin.
• Allergic mechanisms in nervous disease.
• An allosteric rheostat in HIV-1 gp120 reduces CCR5 stoichiometry required for membrane fusion and overcomes diverse entry limitations.
• Development of H activity by human blood-group B substance treated with coffee bean alpha-galactosidase.
• Drug therapy of cerebellar ataxia and disorders of the basal ganglia, based on cerebellar-striatal antagonism.
• Human immunodeficiency virus type 1 Vif functionally interacts with diverse APOBEC3 cytidine deaminases and moves with them between cytoplasmic sites of mRNA metabolism.
• Immunochemical estimation of the rate of disappearance of transfused gamma globulin from the blood in two cases of hypoproteinemia.
• Immunochemical studies on blood groups; the methylpentose contents of hog and human blood group A and O substances and their relationship to cross-reactivity with type XIV antipneumococcus horse serum.
• Permanente Foundation medical bulletin
• Permanente Foundation medical bulletin
• Permanente Foundation medical bulletin
• Pillars Article: An Analysis of the Sequences of the Variable Regions of Bence Jones Proteins and Myeloma Light Chains and their Implications for Antibody Complementarity. J. Exp. Med. 1970. 132: 211-250.
• REM sleep reduction, mood regulation and remission in untreated depression.
• Size and heterogeneity of the combining sites on an antibody molecule.
• Spasticity; its nature and treatment.
• Sterilizing techniques with ethylene oxide.
• Studies on neuromuscular dysfunction; new principles of neuromuscular reeducation.
• The effect of adrenocorticotrophic hormone and X-ray on the amount of circulating antibody.
• The role of drugs in the treatment of cerebral palsy.
• The role of the N-terminal segment of CCR5 in HIV-1 Env-mediated membrane fusion and the mechanism of virus adaptation to CCR5 lacking this segment.
• [Calcium channel blockers in the treatment of arterial hypertension]