Document 0786
 DOCN  M95A0786
 TI    Investigation of the structural components governing the
       polarity-dependent refolding of a CD4-binding peptide from gp120.
 DT    9510
 AU    Graf von Stosch A; Kinzel V; Pipkorn R; Reed J; Department of
       Pathochemistry, Deutsches Krebsforschungszentrum,; Heidelberg, Federal
       Republic of Germany.
 SO    J Mol Biol. 1995 Jul 21;250(4):507-13. Unique Identifier : AIDSLINE
       MED/95341683
 AB    The conformational switch at the principle CD4-binding domain of gp120
       from HIV1 exhibits a highly cooperative folding transition from
       beta-sheet to helix triggered within a very narrow range of solvent
       polarity. The physical basis of this folding behaviour is of interest
       because it is unusual and because it is closely connected with
       biological function, i.e. binding to the CD4 receptor. Previous work
       revealed two primary structural elements, an N-terminal LPCR tetrad and
       a tryptophan residue eight residues C-terminal to this, that were
       essential for the helical and for the beta-sheet conformation,
       respectively. Attempts to construct synthetic switch domains using the
       characteristics so far identified produce peptides undergoing the
       transition at much higher polarity and involving fewer residues than the
       natural domain, in essence a lower stability of the beta-fold to apolar
       conditions. Introduction of a tryptophan residue reduced at the
       C(2)-C(3) linkage demonstrates clearly that the aromatic system of the
       tryptophan residue is central to beta-sheet stabilization. Residues with
       side-chains that might participate in electrostatic or aromatic
       interactions with the pi-electron system of Trp were sequentially
       altered to alanine. The results indicate that the switch properties of
       the CD4-binding domain arise from a poised tension between multiple
       interactions with the Trp aromatic ring stabilizing the beta-structure
       and the tendency of the LPCR tetrad to act as a template for a helical
       fold. Under polar conditions the former dominate. Lowering the polarity
       alters this both by weakening the aromatic interactions and by
       simultaneously increasing the helical propensities of the isoleucine and
       valine side-chains. Tryptophan seems uniquely suited to act as a
       polarity-sensitive conformational sensor.
 DE    Amino Acid Sequence  Antigens, CD4/*METABOLISM  Circular Dichroism
       HIV/*CHEMISTRY  HIV Envelope Protein gp120/*CHEMISTRY/METABOLISM
       Molecular Sequence Data  Mutagenesis
       Peptides/*CHEMISTRY/GENETICS/METABOLISM  Protein Conformation  *Protein
       Folding  Protein Structure, Secondary  Protein Structure, Tertiary
       Tryptophan/CHEMISTRY  JOURNAL ARTICLE

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