PROPENSITY FOR A LEUCINE ZIPPER-LIKE DOMAIN OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 GP41 TO FORM OLIGOMERS CORRELATES WITH A ROLE IN VIRUS-INDUCED FUSION RATHER THAN ASSEMBLY OF THE GLYCOPROTEIN COMPLEX

For a number of viruses, oligomerization is a critical component of en velope processing and surface expression. Previously, we reported that a synthetic peptide (DP-107) corresponding to the putative leucine zi pper region (aa 553-590) of the transmembrane protein (gp41) of human immunodeficiency virus type 1 (HIV-1) exhibited alpha-helical secondar y structure and self-associated as a coiled coil. In view of the tende ncy of this type of structure to mediate protein association, we specu lated that this region of gp41 might play a role in HIV-1 envelope oli gomerization. However, later it was shown that mutations which should disrupt the structural elements of this region of gp41 did not affect envelope processing, transport, or surface expression (assembly oligom erization). In this report we compare the effects of amino acid substi tutions within this coiled-coil region on structure and function of bo th viral envelope proteins and the corresponding synthetic peptides. O ur results establish a correlation between the destabilizing effects o f amino acid substitutions on coiled-coil structure in the peptide mod el and phenotype of virus entry. These biological and physical biochem ical studies do not support a role for the coiled-coil structure in me diating the assembly oligomerization of HIV-1 envelope but do imply th at this region of gp41 plays a key role in the sequence of events asso ciated with viral entry. We propose a functional role for the coiled-c oil domain of HIV-1 gp41.