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Publication Abstract from PubMed

Meprin beta (Mbeta) is a multidomain type-I membrane metallopeptidase that sheds membrane-anchored substrates, releasing their soluble forms. Fetuin-B (FB) is its only known endogenous protein inhibitor. Herein, we analyzed the interaction between the ectodomain of Mbeta (MbetaDeltaC) and FB, which stabilizes the enzyme and inhibits it with subnanomolar affinity. The MbetaDeltaC:FB crystal structure reveals a approximately 250-kDa, approximately 160-A polyglycosylated heterotetrameric particle with a remarkable glycan structure. Two FB moieties insert like wedges through a "CPDCP trunk" and two hairpins into the respective peptidase catalytic domains, blocking the catalytic zinc ions through an "aspartate switch" mechanism. Uniquely, the active site clefts are obstructed from subsites S(4) to S(10)', but S(1) and S(1)' are spared, which prevents cleavage. Modeling of full-length Mbeta reveals an EGF-like domain between MbetaDeltaC and the transmembrane segment that likely serves as a hinge to transit between membrane-distal and membrane-proximal conformations for inhibition and catalysis, respectively.

The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin beta by endogenous fetuin-B.,Eckhard U, Korschgen H, von Wiegen N, Stocker W, Gomis-Ruth FX Proc Natl Acad Sci U S A. 2021 Apr 6;118(14):e2023839118. doi: , 10.1073/pnas.2023839118. PMID:33782129^[2]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.