Proinsulin conversion to desalanyl insulin by α2-macroglobin-bound trypsin

Abstract

HARPEL and Mosesson1 observed that α2-macroglobulin-bound trypsin hydrolysed low molecular weight ester and amide substrates at rates comparable with those of free protease, but degradation of high molecular weight proteins was markedly inhibited. To account for this finding, Barrett and Starkey2 introduced the novel concept of steric entrapment of endopeptidases by α2-macroglobulin. Neurath and Walsh3 have recently reviewed the role of proteolytic enzymes in the conversion of a variety of enzymes, hormones, and other physiologically active proteins from inactive precursors to active forms by limited proteolysis. Many of these physiologically active proteins exist in the bloodstream in both precursor and active forms. We report here that proinsulin, a large polypeptide of 9,000 molecular weight, is rapidly hydrolysed by α2-macroglobulin-bound trypsin. This finding suggests that pro-teases bound to α2-macroglobulin may be involved in limited proteolytic cleavage associated with activation of precursor molecules as well as the degradation of biologically active polypeptides in the circulation.

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LARGMAN, C., JOHNSON, J., BRODRICK, J. et al. Proinsulin conversion to desalanyl insulin by α2-macroglobin-bound trypsin. Nature 269, 168–170 (1977). https://doi.org/10.1038/269168a0

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