VAP2B's metalloprotease-disintegrin-cystine rich (MDC) motif
MDC proteins such as VAP2B are a significant component of snake venom. The MDC motif is conserved in ADAM proteins, both by sequence and structural homology. In snake venom, an integrin binding site lies on the highlighted disintegrin loop.
Using a combination of gene network analysis and gene ontology analysis we identified an enrichment for cell motility and adhesion genes, among the top 5% significance level (p=0.0502) TRA-1-81+ screen hits. Cell motility and lamellipodia formation requires the controlled turnover of actin filament, which is regulated by coronin and RHOC [1-2]. Coronin positively regulates filament assembly, branching, and (in collaboration with RHOC and cofilin) filament disassembly as well; coronin inhibits membrane docking [3-5]. Coronin, RHOC, and actin are all TRA-1-81+ screen hits (CORO1A p=0.0122, CORO1B p=0.0246, ACTG1 p=0.03, RHOC p=0.0302). Other screen hits associated with cell motility and adhesion are MMP14 (p=0.0288), ADAM21 (p=0.0006), and ADAM29 (p=0.0176). MMP14 is involved in cell motility, extracellular matrix degradation, and can be involved in cancer metastasis. MMP14’s metalloprotease domain cleaves cell adhesion molecules such as cadherin and negatively regulates cell adhesion in a context specific fashion [6-7]. ADAM family proteins mediate cleavage of cell adhesion molecules E-cadherin, N-cadherin, epithelial cell adhesion molecule (EpCAM), and PTPμ subfamily receptor protein tyrosine phosphatases (RPTP) in response to ligand binding . ADAMs proteins contain a metalloprotease-disintegrin-cystine rich motif similar to those found in snake venom proteins. ADAM7/21/29's disintegrin domain bears sequence homology to the blood coagulation inhibiting disintegrin domain IPR001762, which is known to regulate integrin dependent cell adhesion .