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 involved in regulation of diverse cellular functions. Positively charged amphipathic helical segments have been identified as an important structural motif in the recognition of CaM by different CaM-activated enzymes and peptides. The carboxyl-terminal domain of the envelope glycoproteins 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-activated enzymes. We show here that synthetic peptide analogs corresponding to the two putative amphipathic helical regions of HIV-1/WMJ gp160 bind to CaM with high affinity (Kd 31-41 nM) in the presence of calcium. They also bind CaM in the absence of calcium, although with much lower affinity. The peptides inhibit CaM-regulated activation of bovine brain phosphodiesterase in vitro. The peptides also inhibit mitogen-induced lymphocyte activation, a property shared by CaM antagonists. Purified HIV-1 gp160 binds to CaM, while gp120, which lacks the putative amphipathic 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 CaM binding by HIV envelope proteins is likely to exert diverse modulatory effects, and the mechanism for HIV-induced cytotoxicity may involve, in part, inhibition of CaM-regulated cellular functions.
Srinivas
S K
SK
Department of Medicine, University of Alabama at Birmingham 35294.
Srinivas
R V
RV
Anantharamaiah
G M
GM
Compans
R W
RW
Segrest
J P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000201:enzymology; D002147:Calmodulin / Q000037:antagonists & inhibitors / Q000378:metabolism*; D002417:Cattle; D003600:Cytosol / Q000378:metabolism; D015686:Gene Products, env / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D019302:HIV Envelope Protein gp160; D015497:HIV-1 / Q000378:metabolism*; D015498:HIV-2 / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008213:Lymphocyte Activation / Q000187:drug effects; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000378:metabolism* / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism; D011485:Protein Binding; D011498:Protein Precursors / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D015302:Simian Immunodeficiency Virus / Q000378:metabolism*; D014759:Viral Envelope Proteins / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology
D002147:Calmodulin; D015686:Gene Products, env; D019302:HIV Envelope Protein gp160; D010446:Peptide Fragments; D010726:Phosphodiesterase Inhibitors; D011498:Protein Precursors; D014759:Viral Envelope Proteins; D010727:Phosphoric Diester Hydrolases