9ggp
From Proteopedia
Alpha-1-antitrypsin in complex with the Fab fragment of an anti-polymer antibody
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 PubMedSerpins, protease inhibitors whose regulated conformational instability renders them susceptible to mutations that cause misfolding, represent a system for the study of non-amyloid protein aggregation. The E342K "Z" variant of alpha-1-antitrypsin (AAT) undergoes oligomeric self-assembly into polymer chains that are associated with liver and lung pathologies in AAT deficiency. Structural characterization of polymers from human tissue has been limited by their heterogeneity and flexibility; here, we have studied their internal structure, which provides insights into the molecular linkage and the pathway by which they are formed. NMR spectra of heat-induced (13)C-ILV-methyl-labeled polymers, and (1)H-methyl spectra of liver-derived polymers, show equivalence to that of AAT in a post-protease-encounter conformation. This is corroborated by x-ray crystallography, which reveals a cryptic epitope recognized by the conformationally selective 2C1 antibody, common to both forms. These data definitively preclude most models of polymerization and are compatible with sequential intermolecular donation of the carboxyl terminus of one molecule into the next during polymer formation. High-resolution characterization of ex vivo AAT polymers by solution-state NMR spectroscopy.,Lowen SM, Waudby CA, Jagger AM, Aldobiyan I, Laffranchi M, Fra A, Christodoulou J, Irving JA, Lomas DA Sci Adv. 2025 May 9;11(19):eadu7064. doi: 10.1126/sciadv.adu7064. Epub 2025 May , 7. PMID:40333971[8] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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