6533b861fe1ef96bd12c4f2d
RESEARCH PRODUCT
The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B
F. Xavier Gomis-rüthNele Von WiegenHagen KörschgenUlrich EckhardWalter Stöckersubject
Multiprotein complexMetallopeptidaseCleavage (embryo)Cell LineMiceProtein structureAnimalsHumansEctoprotein sheddingProtease InhibitorsInhibitionBinding SitesMultidisciplinarybiologyChemistryMetallopeptidaseMetalloendopeptidasesActive siteBiological SciencesSheddaseFetuin-BLepidopteraMolecular Docking SimulationTransmembrane domainEctodomainbiology.proteinBiophysicsProtein structureMultiprotein complexAlzheimer’s diseaseProtein Bindingdescription
Meprin β (Mβ) 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 Mβ (MβΔC) and FB, which stabilizes the enzyme and inhibits it with subnanomolar affinity. The MβΔC:FB crystal structure reveals a ∼250-kDa, ∼160-Å 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 S4 to S10′, but S1 and S1′ are spared, which prevents cleavage. Modeling of full-length Mβ reveals an EGF-like domain between MβΔC and the transmembrane segment that likely serves as a hinge to transit between membrane-distal and membrane-proximal conformations for inhibition and catalysis, respectively.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2021-03-29 |