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.
Highlights
The voltage-dependent anion channel (VDAC) receptor, a major mitochondrial protein, is present in the plasma membrane of normal brain cells
We studied the binding of type plasminogen activator (t-PA) (100 nM) to cells in the presence of antibodies to known t-PA receptors, lipoprotein receptor-related protein receptor (LRP), annexin II, and CD-206 (14 –16), and compared their effect with antibodies against VDAC NH2or COOH-terminal regions
We assessed the antagonistic effect on t-PA binding to SK-N-SH cells with a peptide including amino acid residues 10GKSARDVFTKGYGFGLIKLDL30 (Gly10–Leu30) of the VDAC NH2-terminal region and the amyloid  peptide analogues A 1– 42, A 1–28, A 25–35, A 29 – 40, and A 31– 42, which are known to bind to t-PA [35]
Summary
The VDAC receptor, a major mitochondrial protein, is present in the plasma membrane of normal brain cells. Binding of t-PA to VDAC occurs between a t-PA fibronectin type I finger domain located between amino acids Ile and Asn and a VDAC region including amino acids 20GYGFG24. These VDAC residues correspond to a GXXXG repeat motif commonly found in amyloid  peptides that is necessary for aggregation when these peptides form fibrillar deposits on the cell surface. We 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  peptide deposits from the normal brain and cell debris from injured brain tissue. The voltage-dependent anion channel (VDAC) is a small, 30 –35-kDa protein originally identified in the outer membrane of mitochondria where it functions as the major pore-forming
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