title: Molecular Mechanism of Z α1-Antitrypsin Deficiency.
abstract: The Z mutation (E342K) of α1-antitrypsin (α1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional α1-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 nascent Z α1-AT and why 15% of the expressed Z α1-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 α1-AT. The results reveal that Z α1-AT has a labile strand 5 of the central β-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 β-sheet. This aberrant conformation, induced by the loss of interactions from the Glu-342 side chain, explains why Z α1-AT is prone to polymerization and readily binds to a 6-mer peptide, and it supports that annealing of s5A into the central β-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 α1-AT deficiency.
authors.affiliation: From the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine and University of Chinese Academy of Sciences, Shanghai 200025, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
authors.forename: Fei
authors.initials: F
authors.lastname: Zhang
authors.affiliation: the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
authors.forename: Zhenquan
authors.initials: Z
authors.lastname: Wei
authors.affiliation: the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and.
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.affiliation: the Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Robin W
authors.initials: RW
authors.lastname: Carrell
authors.affiliation: the Department of Haematology, Cambridge Institute for Medical Research, University of Cambridge, Cambridge CB2 0XY, United Kingdom.
authors.forename: Randy J
authors.initials: RJ
authors.lastname: Read
authors.affiliation: From the Institute of Health Sciences, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences and Shanghai Jiao Tong University School of Medicine and University of Chinese Academy of Sciences, Shanghai 200025, China, the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and chengq@shsmu.edu.cn.
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.affiliation: the Hongqiao International Institute of Medicine, Shanghai Tongren Hospital/Faculty of Basic Medicine, Chemical Biology Division of Shanghai Universities E-Institutes, Key Laboratory of Cell Differentiation and Apoptosis of the Chinese Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China, and aiwuzhou@gmail.com.
authors.forename: Aiwu
authors.initials: A
authors.lastname: Zhou
mesh_terms: D019943:Amino Acid Substitution; D018360:Crystallography, X-Ray; D006801:Humans; D020125:Mutation, Missense; D055550:Protein Stability; D017433:Protein Structure, Secondary; D000515:alpha 1-Antitrypsin / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency
chemical_list: D000515:alpha 1-Antitrypsin
keywords: PBA; Polymerization; Z α1-antitrypsin; conformational change; crystal structure; protein folding; serpin; small molecule