Alpha-1-antitrypsin deficiency, the serpinopathies and conformational disease.
Alpha-1-antitrypsin deficiency results from point mutations that distort the structure of the protein to allow a unique protein-protein interaction that we have termed loopsheet polymerisation. Polymers of Z alpha 1-antitrypsin accumulate within hepatocytes to form inclusion bodies that are associated with juvenile cirrhosis and hepatocellular carcinoma. The lack of circulating protein predisposes the Z alpha 1-antitrypsin homozygote to emphysema. This process also occurs in other members of the serine proteinase inhibitor (serpin) superfamily, antithrombin, C1-inhibitor and alpha 1-antichymotrypsin, in association with thrombosis, angioedema and chronic obstructive pulmonary disease, respectively, and we have recently shown that it underlies a novel inclusion body dementia. The interaction provides a useful paradigm for other 'conformational diseases' such as Huntington's disease, Creutzfeldt-Jakob disease and the amyloidoses.
Parmar
J S
JS
Cambridge Institute for Medical Research. jsp35@hermes.cam.ac.uk
Lomas
D A
DA
D000686:Amyloidosis / Q000503:physiopathology*; D007562:Creutzfeldt-Jakob Syndrome / Q000503:physiopathology*; D006801:Humans; D006816:Huntington Disease / Q000503:physiopathology*; D002479:Inclusion Bodies; D011108:Polymers; D011487:Protein Conformation; D015843:Serpins / Q000494:pharmacology*; D000515:alpha 1-Antitrypsin / Q000737:chemistry*; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000503:physiopathology
D011108:Polymers; D015843:Serpins; D000515:alpha 1-Antitrypsin