title: The molecular and cellular pathology of α₁-antitrypsin deficiency.
abstract: Since its discovery 50 years ago, α₁-antitrypsin deficiency has represented a case study in molecular medicine, with careful clinical characterisation guiding genetic, biochemical, biophysical, structural, cellular, and in vivo studies. Here we highlight the milestones in understanding the disease mechanisms and show how they have spurred the development of novel therapeutic strategies. α₁-Antitrypsin deficiency is an archetypal conformational disease. Its pathogenesis demonstrates the interplay between protein folding and quality control mechanisms, with aberrant conformational changes causing liver and lung disease through combined loss- and toxic gain-of-function effects. Moreover, α₁-antitrypsin exemplifies the ability of diverse proteins to self-associate into a range of morphologically distinct polymers, suggesting a mechanism for protein and cell evolution.
authors.affiliation: Division of Asthma, Allergy, and Lung Biology, King's College London, 5th Floor, Tower Wing, Guy's Hospital, London, SE1 9RT, UK; Institute of Structural and Molecular Biology/Crystallography, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK.
authors.forename: Bibek
authors.initials: B
authors.lastname: Gooptu
authors.affiliation: Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Cambridge, CB2 0XY, UK.
authors.forename: Jennifer A
authors.initials: JA
authors.lastname: Dickens
authors.affiliation: Institute of Structural and Molecular Biology/Crystallography, Department of Biological Sciences, Birkbeck College, University of London, Malet Street, London, WC1E 7HX, UK; Division of Medicine, University College London, 1st Floor, Maple House, 149, Tottenham Court Road, London, W1T 7NF, UK. Electronic address: d.lomas@ucl.ac.uk.
authors.forename: David A
authors.initials: DA
authors.lastname: Lomas
mesh_terms: D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism; D006801:Humans; D055503:Protein Multimerization; D011499:Protein Processing, Post-Translational; D059748:Proteolysis; D056811:Unfolded Protein Response; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D019896:alpha 1-Antitrypsin Deficiency / Q000209:etiology* / Q000473:pathology* / Q000628:therapy
chemical_list: D000515:alpha 1-Antitrypsin
keywords: cirrhosis; conformational disease; emphysema; misfolding; protein evolution; α(1)-antitrypsin deficiency