气候变化领域集成服务门户(CCPortal): The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B

CCPortal

DOI	10.1073/pnas.2023839118
	The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B
	Eckhard U.; Körschgen H.; von Wiegen N.; Stöcker W.; Gomis-Rüth F.X.
发表日期	2021
ISSN	00278424
卷号	118 期号:14
英文摘要	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 membranedistal and membrane-proximal conformations for inhibition and catalysis, respectively. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Alzheimer's disease; Ectoprotein shedding; Metallopeptidase inhibition; Multiprotein complex; Protein structure
语种	英语
scopus关键词	epidermal growth factor; fetuin B; glycan; metalloproteinase; peptidase; protein meprin beta; unclassified drug; zinc ion; Article; binding affinity; catalysis; controlled study; crystal structure; enzyme active site; enzyme conformation; enzyme inhibition; enzyme stability; human; mouse; nonhuman; priority journal; protein domain; protein protein interaction
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180018
作者单位	Proteolysis Laboratory, Department of Structural Biology, Molecular Biology Institute of Barcelona Higher Scientific Research Council, Barcelona Science Park, Barcelona, 08028, Spain; Institut für Molekulare Physiologie, Johannes Gutenberg Universität Mainz, Mainz, 55128, Germany
推荐引用方式 GB/T 7714	Eckhard U.,Körschgen H.,von Wiegen N.,et al. The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B[J],2021,118(14).
APA	Eckhard U.,Körschgen H.,von Wiegen N.,Stöcker W.,&Gomis-Rüth F.X..(2021).The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B.Proceedings of the National Academy of Sciences of the United States of America,118(14).
MLA	Eckhard U.,et al."The crystal structure of a 250-kDa heterotetrameric particle explains inhibition of sheddase meprin β by endogenous fetuin-B".Proceedings of the National Academy of Sciences of the United States of America 118.14(2021).