5io1
CRYSTAL STRUCTURE OF RECOMBINANT HUMAN Z ALPHA-1-ANTITRYPSINCRYSTAL STRUCTURE OF RECOMBINANT HUMAN Z ALPHA-1-ANTITRYPSIN
Structural highlights
DiseaseA1AT_HUMAN Defects in SERPINA1 are the cause of alpha-1-antitrypsin deficiency (A1ATD) [MIM:613490. A disorder whose most common manifestation is emphysema, which becomes evident by the third to fourth decade. A less common manifestation of the deficiency is liver disease, which occurs in children and adults, and may result in cirrhosis and liver failure. Environmental factors, particularly cigarette smoking, greatly increase the risk of emphysema at an earlier age.[1] [2] [3] FunctionA1AT_HUMAN Inhibitor of serine proteases. Its primary target is elastase, but it also has a moderate affinity for plasmin and thrombin. Irreversibly inhibits trypsin, chymotrypsin and plasminogen activator. The aberrant form inhibits insulin-induced NO synthesis in platelets, decreases coagulation time and has proteolytic activity against insulin and plasmin.[:][4] [5] Short peptide from AAT: reversible chymotrypsin inhibitor. It also inhibits elastase, but not trypsin. Its major physiological function is the protection of the lower respiratory tract against proteolytic destruction by human leukocyte elastase (HLE).[:][6] [7] Publication Abstract from PubMedThe Z mutation (E342K) of alpha1-antitrypsin (alpha1-AT), carried by 4% of Northern Europeans, predisposes to early onset of emphysema due to decreased functional alpha1-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 alpha1-AT and why 15% of the expressed Z alpha1-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 alpha1-AT. The results reveal that Z alpha1-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 alpha1-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 alpha1-AT deficiency. Molecular Mechanism of Z alpha1-Antitrypsin Deficiency.,Huang X, Zheng Y, Zhang F, Wei Z, Wang Y, Carrell RW, Read RJ, Chen GQ, Zhou A J Biol Chem. 2016 Jul 22;291(30):15674-86. doi: 10.1074/jbc.M116.727826. Epub, 2016 May 31. PMID:27246852[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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