Multimerin: a bench-to-bedside chronology of a unique platelet and endothelial cell protein--from discovery to function to abnormalities in disease.
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In studies conducted about 8 years ago, the author and her colleagues raised a monoclonal antibody that recognized an uncharacterized human platelet protein with a reduced molecular mass of 155 kDa. Investigations of this protein's nonreduced structure yielded surprising findings: in its native state, it exists as massive disulfide-linked multimers millions of daltons in size, making it one of the largest proteins found in the human body. This feature led the author to designate this protein "multimerin." Multimerin is found in endothelial cells as well as in platelets. It originates from a single subunit protein, promultimerin, that undergoes extensive N-glycosylation, proteolytic processing and polymerization during biosynthesis. Recent data from the cloning and sequencing of its complementary DNA indicate that multimerin is a unique protein. Like von Willebrand factor, it has a massive repeating structure, but these proteins are unrelated. Multimerin's sequence contains the adhesive motif Arg-Gly-Asp-Ser, central coiled-coil sequences, several epidermal growth-factor-like motifs, and a globular domain that is similar to a protein-binding domain found in complement C1q and in collagens type VIII and X. Investigations of multimerin's function indicate that it binds the coagulation protein factor V and its activated form, factor Va. In platelets, but not in plasma, all of the biologically active factor V is complexed with multimerin. Multimerin may also have functions as an extracellular matrix or adhesive protein. Recently, members of 2 Canadian families with puzzling autosomal-dominant bleeding disorders were found to have a deficiency of platelet multimerin. Studies of these patients may provide a unique opportunity to evaluate the functions of multimerin.
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