The voltage-dependent anion channel is a receptor for plasminogen kringle 5 on human endothelial cells.
Human plasminogen contains structural domains that are termed kringles. Proteolytic cleavage of plasminogen yields kringles 1-3 or 4 and kringle 5 (K5), which regulate endothelial cell proliferation. The receptor for kringles 1-3 or 4 has been identified as cell surface-associated ATP synthase; however, the receptor for K5 is not known. Sequence homology exists between the plasminogen activator streptokinase and the human voltage-dependent anion channel (VDAC); however, a functional relationship between these proteins has not been reported. A streptokinase binding site for K5 is located between residues Tyr252-Lys283, which is homologous to the primary sequence of VDAC residues Tyr224-Lys255. Antibodies against these sequences react with VDAC and detect this protein on the plasma membrane of human endothelial cells. K5 binds with high affinity (Kd of 28 nm) to endothelial cells, and binding is inhibited by these antibodies. Purified VDAC binds to K5 but only when reconstituted into liposomes. K5 also interferes with mechanisms controlling the regulation of intracellular Ca2+ via its interaction with VDAC. K5 binding to endothelial cells also induces a decrease in intracellular pH and hyperpolarization of the mitochondrial membrane. These studies suggest that VDAC is a receptor for K5.
Gonzalez-Gronow
Mario
M
Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. gonza002@mc.duke.edu
Kalfa
Theodosia
T
Johnson
Carrie E
CE
Gawdi
Govind
G
Pizzo
Salvatore V
SV
D000595:Amino Acid Sequence; D001665:Binding Sites / Q000235:genetics; D002478:Cells, Cultured; D004730:Endothelium, Vascular / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D066298:In Vitro Techniques; D007700:Kinetics; D018082:Kringles; D008081:Liposomes; D008564:Membrane Potentials; D008928:Mitochondria / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010958:Plasminogen / Q000737:chemistry* / Q000378:metabolism*; D018272:Porins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D011956:Receptors, Cell Surface / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D055293:Receptors, Urokinase Plasminogen Activator; D017386:Sequence Homology, Amino Acid; D013300:Streptokinase / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D050994:Voltage-Dependent Anion Channels
D008081:Liposomes; C524898:PLAUR protein, human; D018272:Porins; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; D050994:Voltage-Dependent Anion Channels; D010958:Plasminogen; D013300:Streptokinase