title: Buried polar interactions and conformational stability in the simian immunodeficiency virus (SIV) gp41 core.
abstract: For human (HIV) and simian (SIV) immunodeficiency viruses, the gp41 envelope protein undergoes a receptor-activated conformational change from a labile native structure to an energetically more stable fusogenic conformation, which then mediates viral-cell membrane fusion. The core structure of fusion-active gp41 is a six-helix bundle in which three antiparallel carboxyl-terminal helices are packed against an amino-terminal trimeric coiled coil. Here we show that a recombinant model of the SIV gp41 core, designated N36(L6)C34, forms an alpha-helical trimer that exhibits a cooperative two-state folding-unfolding transition. We investigate the importance of buried polar interactions in determining the overall fold of the gp41 core. We have replaced each of four polar amino acids at the heptad a and d positions of the coiled coil in N36(L6)C34 with a representative hydrophobic amino acid, isoleucine. The Q565I, T582I, and T586I variants form six-helix bundle structures that are significantly more stable than that of the wild-type peptide, whereas the Q575I variant misfolds into an insoluble aggregate under physiological conditions. Thus, the buried polar residues within the amino-terminal heptad repeat are important determinants of the structural specificity and stability of the gp41 core. We suggest that these conserved buried polar interactions play a role in governing the conformational state of the gp41 molecule.
authors.affiliation: Department of Biochemistry, Weill Medical College of Cornell University, New York, New York 10021, USA.
authors.forename: H
authors.initials: H
authors.lastname: Ji
authors.forename: C
authors.initials: C
authors.lastname: Bracken
authors.forename: M
authors.initials: M
authors.lastname: Lu
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution / Q000235:genetics; D000818:Animals; D002942:Circular Dichroism; D005973:Glutamine / Q000235:genetics; D007532:Isoleucine / Q000235:genetics; D008251:Macaca; D008562:Membrane Glycoproteins / Q000737:chemistry* / Q000235:genetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010446:Peptide Fragments / Q000737:chemistry* / Q000235:genetics; D011487:Protein Conformation; D017510:Protein Folding; D017433:Protein Structure, Secondary; D011994:Recombinant Proteins / Q000737:chemistry; D012191:Retroviridae Proteins / Q000737:chemistry* / Q000235:genetics; D015302:Simian Immunodeficiency Virus / Q000737:chemistry*; D013816:Thermodynamics; D013912:Threonine / Q000235:genetics; D014759:Viral Envelope Proteins / Q000737:chemistry* / Q000235:genetics
chemical_list: D008562:Membrane Glycoproteins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D012191:Retroviridae Proteins; C082614:SIV envelope protein gp41; D014759:Viral Envelope Proteins; D007532:Isoleucine; D005973:Glutamine; D013912:Threonine