Source:http://linkedlifedata.com/resource/pubmed/id/17526486
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rdf:type | |
lifeskim:mentions | |
pubmed:issue |
32
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pubmed:dateCreated |
2007-8-6
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pubmed:abstractText |
The binding of CD4 and chemokine receptors to the gp120 attachment glycoprotein of human immunodeficiency virus triggers refolding of the associated gp41 fusion glycoprotein into a trimer of hairpins with a 6-helix bundle (6HB) core. These events lead to membrane fusion and viral entry. Here, we examined the functions of the fusion peptide-proximal polar segment and membrane-proximal Trp-rich region (MPR), which are exterior to the 6HB. Alanine substitution of Trp(666), Trp(672), Phe(673), and Ile(675) in the MPR reduced entry by up to 120-fold without affecting gp120-gp41 association or cell-cell fusion. The L537A polar segment mutation led to the loss of gp120 from the gp120-gp41 complex, reduced entry by approximately 10-fold, but did not affect cell-cell fusion. Simultaneous Ala substitution of Leu(537) with Trp(666), Trp(672), Phe(673), or Ile(675) abolished entry with 50-80% reductions in cell-cell fusion. gp120-gp41 complexes of fusion-defective double mutants were resistant to soluble CD4-induced shedding of gp120, suggesting that their ability to undergo receptor-induced conformational changes was compromised. Consistent with this idea, a representative mutation, L537A/W666A, led to an approximately 80% reduction in lipophilic fluorescent dye transfer between gp120-gp41-expressing cells and receptor-expressing targets, indicating a block prior to the lipid-mixing phase. The L537A/W666A double mutation increased the chymotrypsin sensitivity of the polar segment in a trimer of hairpins model, comprising the 6HB core, the polar segment, and MPR linked N-terminally to maltose-binding protein. The data indicate that the polar segment and MPR of gp41 act synergistically in forming a fusion-competent gp120-gp41 complex and in stabilizing the membrane-interactive end of the trimer of hairpins.
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pubmed:language |
eng
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pubmed:journal | |
pubmed:citationSubset |
IM
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pubmed:chemical |
http://linkedlifedata.com/resource/pubmed/chemical/Alanine,
http://linkedlifedata.com/resource/pubmed/chemical/Glycoproteins,
http://linkedlifedata.com/resource/pubmed/chemical/HIV Envelope Protein gp120,
http://linkedlifedata.com/resource/pubmed/chemical/HIV Envelope Protein gp41,
http://linkedlifedata.com/resource/pubmed/chemical/Leucine,
http://linkedlifedata.com/resource/pubmed/chemical/Recombinant Fusion Proteins
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pubmed:status |
MEDLINE
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pubmed:month |
Aug
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pubmed:issn |
0021-9258
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pubmed:author | |
pubmed:issnType |
Print
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pubmed:day |
10
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pubmed:volume |
282
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pubmed:owner |
NLM
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pubmed:authorsComplete |
Y
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pubmed:pagination |
23104-16
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pubmed:meshHeading |
pubmed-meshheading:17526486-Alanine,
pubmed-meshheading:17526486-Amino Acid Sequence,
pubmed-meshheading:17526486-CD4-Positive T-Lymphocytes,
pubmed-meshheading:17526486-Cell Line,
pubmed-meshheading:17526486-Dimerization,
pubmed-meshheading:17526486-Genetic Vectors,
pubmed-meshheading:17526486-Glycoproteins,
pubmed-meshheading:17526486-HIV Envelope Protein gp120,
pubmed-meshheading:17526486-HIV Envelope Protein gp41,
pubmed-meshheading:17526486-Humans,
pubmed-meshheading:17526486-Leucine,
pubmed-meshheading:17526486-Molecular Sequence Data,
pubmed-meshheading:17526486-Protein Structure, Tertiary,
pubmed-meshheading:17526486-Recombinant Fusion Proteins,
pubmed-meshheading:17526486-Sequence Homology, Amino Acid
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pubmed:year |
2007
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pubmed:articleTitle |
Functional links between the fusion peptide-proximal polar segment and membrane-proximal region of human immunodeficiency virus gp41 in distinct phases of membrane fusion.
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pubmed:affiliation |
Macfarlane Burnet Institute for Medical Research and Public Health, Prahran, Victoria 3004, Australia.
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pubmed:publicationType |
Journal Article,
Research Support, Non-U.S. Gov't
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