Mastin is a gelatinolytic mast cell peptidase resembling a mini-proteasome.
Mastin is a tryptic peptidase secreted by canine mast cells. This work reveals that mastin is composed of catalytic domain singlets and disulfide-linked dimers. Monomers unite non-covalently to form tryptase-like tetramers, whereas dimers aggregate with monomers into larger clusters stabilized by hydrophobic contacts. Unlike tryptases, mastin resists inactivation by leech-derived tryptase inhibitor, indicating a smaller central cavity, as confirmed by structural models. Nonetheless, mastin is strongly gelatinolytic while not cleaving native collagen or casein, suggesting a preference for denatured proteins threaded into its central cavity. Phylogenetic analysis suggests that mammalian mastins shared more recent ancestors with soluble alpha/beta/delta tryptases than with membrane-anchored gamma-tryptases, and diverged more rapidly. We hypothesize that gelatinase activity and formation of inhibitor-resistant oligomers are ancestral characteristics shared by soluble tryptases and mastins, and that secreted mastin is a mini-proteasome-like complex that breaks down partially degraded proteins without causing bystander damage to intact, native proteins.
Raymond
Wilfred W
WW
Department of Medicine, Cardiovascular Research Institute, University of California at San Francisco, San Francisco, CA 94143-0911, USA.
Sommerhoff
Christian P
CP
Caughey
George H
GH
D000595:Amino Acid Sequence; D000818:Animals; D002364:Caseins / Q000378:metabolism; D020134:Catalytic Domain / Q000187:drug effects; D003094:Collagen / Q000378:metabolism; D019281:Dimerization; D004285:Dogs; D005780:Gelatin / Q000378:metabolism*; D015723:Gene Library; D006801:Humans; D008407:Mast Cells / Q000187:drug effects / Q000201:enzymology* / Q000378:metabolism; D008958:Models, Molecular; D008969:Molecular Sequence Data; D010802:Phylogeny; D011480:Protease Inhibitors / Q000494:pharmacology; D046988:Proteasome Endopeptidase Complex / Q000187:drug effects / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D012697:Serine Endopeptidases / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D013379:Substrate Specificity
D002364:Caseins; D011480:Protease Inhibitors; D005780:Gelatin; D003094:Collagen; D012697:Serine Endopeptidases; D046988:Proteasome Endopeptidase Complex