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	Molecular mechanism of z alpha 1-antitrypsin deficiency
	Huang, Xin1,2,3; Zheng, Ying4; Zhang, Fei4; Wei, Zhenquan4; Wang, Yugang4; Carrell, Robin W.5; Read, Randy J.5; Chen, Guo-Qiang1,2,3,4; Zhou, Aiwu4
刊名	Journal of biological chemistry
	2016-07-22
卷号	291期号:30页码:15674-15686
ISSN号	0021-9258
DOI	10.1074/jbc.m116.727826
通讯作者	Chen, guo-qiang(chengq@shsmu.edu.cn) ; Zhou, aiwu(aiwuzhou@gmail.com)
英文摘要	The z mutation (e342k) of alpha 1-antitrypsin (alpha 1-at), carried by 4% of northern europeans, predisposes to early onset of emphysema due to decreased functional alpha 1-at in the lung and to liver cirrhosis due to accumulation of polymers in hepatocytes. however, it remains unclear why the z mutation causes intracellular polymerization of nascentz alpha 1-at and why 15% of the expressed z alpha 1-at is secreted into circulation as functional, but polymerogenic, monomers. here, we solve the crystal structure of the z-monomer and have engineered replacements to assess the conformational role of residue glu-342 in alpha 1-at. the results reveal that z alpha 1-at has a labile strand 5 of the central beta-sheet a (s5a) with a consequent equilibrium between a native inhibitory conformation, as in its crystal structure here, and an aberrant conformation with s5a only partially incorporated into the central beta-sheet. this aberrant conformation, induced by the loss of interactions from the glu-342 side chain, explains why z alpha 1-at is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5a into the central beta-sheet is a crucial step in the serpins' metastable conformational formation. the demonstration that the aberrant conformation can be rectified through stabilization of the labile s5a by binding of a small molecule opens a potential therapeutic approach for z alpha 1-at deficiency.
WOS关键词	ALPHA(1)-ANTITRYPSIN DEFICIENCY ; SERPIN POLYMERIZATION ; ALPHA-1-PROTEINASE INHIBITOR ; CONFORMATIONAL DISEASE ; ANGSTROM STRUCTURE ; CRYSTAL-STRUCTURE ; SALT BRIDGE ; SECRETION ; DEFECT ; LOOP
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
语种	英语
出版者	AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
WOS记录号	WOS:000380584200022
内容类型	期刊论文
URI标识	http://www.corc.org.cn/handle/1471x/2374489
专题	中国科学院大学
通讯作者	Chen, Guo-Qiang; Zhou, Aiwu
作者单位	1.Chinese Acad Sci, Inst Hlth Sci, Shanghai Inst Biol Sci, Shanghai 200025, Peoples R China 2.Shanghai Jiao Tong Univ, Sch Med, Shanghai 200025, Peoples R China 3.Univ Chinese Acad Sci, Shanghai 200025, Peoples R China 4.Shanghai Jiao Tong Univ, Hongqiao Int Inst Med,Shanghai Tongren Hosp,Sch M, Fac Basic Med,Chem Biol Div Shanghai Univ E Inst, Key Lab Cell Differentiat & Apoptosis,Chinese Min, Shanghai 200025, Peoples R China 5.Univ Cambridge, Cambridge Inst Med Res, Dept Haematol, Cambridge CB2 0XY, England
推荐引用方式 GB/T 7714	Huang, Xin,Zheng, Ying,Zhang, Fei,et al. Molecular mechanism of z alpha 1-antitrypsin deficiency[J]. Journal of biological chemistry,2016,291(30):15674-15686.
APA	Huang, Xin.,Zheng, Ying.,Zhang, Fei.,Wei, Zhenquan.,Wang, Yugang.,...&Zhou, Aiwu.(2016).Molecular mechanism of z alpha 1-antitrypsin deficiency.Journal of biological chemistry,291(30),15674-15686.
MLA	Huang, Xin,et al."Molecular mechanism of z alpha 1-antitrypsin deficiency".Journal of biological chemistry 291.30(2016):15674-15686.

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