title: The voltage-dependent anion channel (VDAC) binds tissue-type plasminogen activator and promotes activation of plasminogen on the cell surface.
abstract: The voltage-dependent anion channel (VDAC), a major pore-forming protein in the outer membrane of mitochondria, is also found in the plasma membrane of a large number of cells where in addition to its role in regulating cellular ATP release and volume control it is important for maintaining redox homeostasis. Cell surface VDAC is a receptor for plasminogen kringle 5, which promotes partial closure of the channel. In this study, we demonstrate that VDAC binds tissue-type plasminogen activator (t-PA) on human neuroblastoma SK-N-SH cells. Binding of t-PA to VDAC induced a decrease in K(m) and an increase in the V(max) for activation of its substrate, plasminogen (Pg). This resulted in accelerated Pg activation when VDAC, t-PA, and Pg were bound together. VDAC is also a substrate for plasmin; hence, it mimics fibrin activity. Binding of t-PA to VDAC occurs between a t-PA fibronectin type I finger domain located between amino acids Ile(5) and Asn(37) and a VDAC region including amino acids (20)GYGFG(24). These VDAC residues correspond to a GXXXG repeat motif commonly found in amyloid β peptides that is necessary for aggregation when these peptides form fibrillar deposits on the cell surface. Furthermore, we also show that Pg kringle 5 is a substrate for the NADH-dependent reductase activity of VDAC. This ternary complex is an efficient proteolytic complex that may facilitate removal of amyloid β peptide deposits from the normal brain and cell debris from injured brain tissue.
authors.affiliation: Department of Pathology, Duke University Medical Center, Durham, North Carolina 27710, USA. gonza002@mc.duke.edu
authors.forename: Mario
authors.initials: M
authors.lastname: Gonzalez-Gronow
authors.forename: Rupa
authors.initials: R
authors.lastname: Ray
authors.forename: Fang
authors.initials: F
authors.lastname: Wang
authors.forename: Salvatore V
authors.initials: SV
authors.lastname: Pizzo
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D017209:Apoptosis; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D002845:Chromatography / Q000379:methods; D005341:Fibrinolysin / Q000378:metabolism; D005342:Fibrinolysis; D006358:Hot Temperature; D006801:Humans; D007700:Kinetics; D008957:Models, Genetic; D010958:Plasminogen / Q000378:metabolism*; D011485:Protein Binding; D010959:Tissue Plasminogen Activator / Q000378:metabolism*; D050994:Voltage-Dependent Anion Channels / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D050994:Voltage-Dependent Anion Channels; D010958:Plasminogen; D010959:Tissue Plasminogen Activator; D005341:Fibrinolysin