The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B

• DOI: 10.1073/pnas.2023839118
• Publication Date: 2021-03-29T20:26:22Z
• Authors: Ulrich Eckhard; Hagen Körschgen; Nele von Wiegen; Walter Stöcker; F. Xavier Gomis-Rüth
• Keywords: 0303 health sciences; Binding Sites; Metallopeptidase; Metalloendopeptidases; Fetuin-B; Cell Line; Lepidoptera; Molecular Docking Simulation; Mice; 03 medical and health sciences; Protein structure; Ectoprotein shedding; Animals; Humans; Protease Inhibitors; Multiprotein complex; Alzheimer’s disease; Inhibition; Protein Binding

Significance Membrane-bound metallopeptidases cut substrates as “sheddases” on the cell surface. Due to the irreversibility of peptide bond cleavage, they are regulated by specific, colocalizing protein inhibitors. We solved the crystal structure of the complex between the ectomoiety of the human integral membrane sheddase, meprin β (Mβ), and its only reported endogenous protein inhibitor, fetuin-B (FB), which reveals a large particle of ∼250-kDa and ∼160-Å maximal dimension. Our results unveiled a sophisticated “raised elephant trunk” mechanism as the structural basis for the very strong inhibition of Mβ by FB. Moreover, we derived a functional model for Mβ on the cell membrane, which foresees a transition between a membrane-proximal and a membrane-distal position for catalytic and inhibitory functions, respectively.