IDENTIFICATION OF A CALMODULIN-BINDING AND INHIBITORY PEPTIDE DOMAIN IN THE HIV-1 TRANSMEMBRANE GLYCOPROTEIN

A number of studies suggest a critical rot of the HIV-1 envelope glyco protein in cytopathogenesis, but the detailed mechanisms of cell injur y remain to be defined. HIV-1 envelope proteins associate with the hos t cell membrane, and studies have demonstrated that HIV perturbs membr ane structure and function. We describe here a structurally conserved region of the HIV-1 transmembrane protein (TM) that displays functiona l properties of target regions of proteins that interact directly with calcium-saturated calmodulin as part of cellular response cascades. T he synthetic peptide homolog encompassing the carboxyl terminus (amino acid residues 828-855) of HIV-1 TM protein (LLP-1) is shown in standa rd in vitro assays to bind efficiently to purified calmodulin (CaM) an d to inhibit in vitro CaM-mediated stimulation of phosphodiesterase ac tivity. This suggests that this peptide homolog binds to CaM at affini ties similar to those reported for a reference CaM-binding peptide. In addition, the CaM-dependent process of phospholipid synthesis can be inhibited in cell cultures by exogenous addition of the LLP-1. Finally , we have shown that the full-length TM protein binds CaM, whereas a t runcated TM protein lacking the LLP-1 segment does not bind CaM. These results suggest a novel mechanism of viral cytopathogenesis mediated by the interaction of HIV-1TM protein with cellular CaM, that could le ad to an uncoupling of critical cellular signal transduction pathways.