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Structure of the astacin zymogen of LAST-MAM from Limulus polyphemus
Structural highlights
FunctionB4F320_LIMPO Zinc metalloprotease. Provoques deadhesion of endothelial cells from cell cultures, and also degradation of fibronectin, fibrinogen and gelatin in vitro. Its role in the venom is not fully understood but it might act as a spreading factor that facilitates diffusion of other venom toxins. Alternatively, it might be involved in the proteolytic processing of other venom toxins or it might play a role in extra-oral digestion of prey.[ARBA:ARBA00025529] Publication Abstract from PubMedThe horseshoe crab Limulus polyphemus is one of few extant Limulus species, which date back to approximately 250 million years ago under the conservation of a common Bauplan documented by fossil records. It possesses the only proteolytic blood-coagulation and innate immunity system outside vertebrates and is a model organism for the study of the evolution and function of peptidases. The astacins are a family of metallopeptidases that share a central approximately 200-residue catalytic domain (CD), which is found in >1000 species across holozoans and, sporadically, bacteria. Here, the zymogen of an astacin from L. polyphemus was crystallized and its structure was solved. A 34-residue, mostly unstructured pro-peptide (PP) traverses, and thus blocks, the active-site cleft of the CD in the opposite direction to a substrate. A central ;PP motif' (F(35)-E-G-D-I(39)) adopts a loop structure which positions Asp38 to bind the catalytic metal, replacing the solvent molecule required for catalysis in the mature enzyme according to an ;aspartate-switch' mechanism. Maturation cleavage of the PP liberates the cleft and causes the rearrangement of an ;activation segment'. Moreover, the mature N-terminus is repositioned to penetrate the CD moiety and is anchored to a buried ;family-specific' glutamate. Overall, this mechanism of latency is reminiscent of that of the other three astacins with known zymogenic and mature structures, namely crayfish astacin, human meprin beta and bacterial myroilysin, but each shows specific structural characteristics. Remarkably, myroilysin lacks the PP motif and employs a cysteine instead of the aspartate to block the catalytic metal. Zymogenic latency in an approximately 250-million-year-old astacin metallopeptidase.,Guevara T, Rodriguez-Banqueri A, Stocker W, Becker-Pauly C, Gomis-Ruth FX Acta Crystallogr D Struct Biol. 2022 Nov 1;78(Pt 11):1347-1357. doi: , 10.1107/S2059798322009688. Epub 2022 Oct 20. PMID:36322418[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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