Trimerization specificity in HIV-1 gp41: Analysis with a GCN4 leucine zipper model

The envelope glycoprotein of human immunodeficiency virus type 1 (HIV-1) co nsists of a complex of two noncovalently associated subunits, gp120 and gp4 1. Formation of gp120/gp41 oligomers is thought to be dependent on a 4-3 hy drophobic (heptad) repeat located in the amino-terminal region of the gp41 molecule. We have investigated the role of this heptad repeat in determinin g the oligomeric structure of gp41 by introducing its buried core residues into the first (a) and fourth (d) positions of the GCN4 leucine-zipper dime rization domain. The mutant peptides fold into trimeric, helical structures , as shown by circular dichroism and equilibrium sedimentation centrifugati on. The 2.4 Angstrom resolution crystal structure of one such trimer reveal s a parallel three-stranded, a-helical coiled coil. Thus, the buried core r esidues from the gp41 heptad repeat direct trimer formation. We suggest tha t the conserved aminoterminal heptad repeat within the gp41 ectodomain poss esses trimerization specificity.