CYTOSOLIC DOMAIN OF THE HUMAN-IMMUNODEFICIENCY-VIRUS ENVELOPE GLYCOPROTEINS BINDS TO CALMODULIN AND INHIBITS CALMODULIN-REGULATED PROTEINS

Calmodulin (CaM), the major intracellular receptor for calcium, is inv olved in regulation of diverse cellular functions. Positively charged amphipathic helical segments have been identified as an important stru ctural motif in the recognition of CaM by different CaM-activated enzy mes and peptides. The carboxyl-terminal domain of the envelope glycopr oteins of human and simian immunodeficiency viruses (HIV-1, HIV-2, and SIV) contain regions that can fold into amphipathic helical segments, which closely resemble the amphipathic segments found in CaM-activate d enzymes. We show here that synthetic peptide analogs corresponding t o the two putative amphipathic helical regions of HIV-1/WMJ gp160 bind to CaM with high affinity (K(d) 31-41 nM) in the presence of calcium. They also bind CaM in the absence of calcium, although with much lowe r affinity. The peptides inhibit CaM-regulated activation of bovine br ain phosphodiesterase in vitro. The peptides also inhibit mitogen-indu ced lymphocyte activation, a property shared by CaM antagonists. Purif ied HIV-1 gp160 binds to CaM, while gp120, which lacks the putative am phipathic helical segments, does not bind CaM. In HIV-infected cells, the putative CaM-binding regions of gp160 are located intracellularly and may therefore interact with the cytosolic CaM. We postulate that C aM binding by HIV envelope proteins is likely to exert diverse modulat ory effects, and the mechanism for HIV-induced cytotoxicity may involv e, in part, inhibition of CaM-regulated cellular functions.