PRIMARY STRUCTURE ELEMENTS RESPONSIBLE FOR THE CONFORMATIONAL SWITCH IN THE ENVELOPE GLYCOPROTEIN GP120 FROM HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 - LPCR IS A MOTIF GOVERNING FOLDING

The ability to undergo a particular conformational switch on moving fr om a polar to a less polar environment has been shown to be conserved at the CD4-binding domain of the envelope glycoprotein gp120 from huma n immunodeficiency virus type 1 despite considerable variability in pr imary structure and is essential for the process of binding to the T-c ell receptor CD4. The elements necessary to the expression of this beh avior have been examined in synthetic peptides using circular dichrois m and have been found to include a tetrad, LPCR, plus a tryptophan at a position 8 residues C-terminal to it. In the absence of the tryptoph an the conformational change from beta-sheet to alpha-helix as medium polarity decreases does not occur abruptly but, rather, in a linear fa shion. In the absence of the LPCR tetrad, no transition to alpha-helix occurs even at 100% trifluoroethanol. These two domains interact to c ontrol not only the beta --> alpha transition but also both its cooper ativity and the critical point on the polar --> apolar gradient at whi ch it occurs. Sequence similarity searches of the protein data banks s uggest that an LPCR tetrad, governing the folding behavior of subseque nt residues, may occur as a conserved motif in proteins in general. Sy nthetic peptides with the sequence of non-gp120 proteins that contain the tetrad do in fact display a similar pattern of folding response to decreasing polarity, with a sharp, cooperative transition from beta-s heet to alpha-helix. The LPCR tetrad appears to be a motif that contro ls secondary structure in a manner supplementary to that predicted by folding algorithms.