Heteropolymerization of S, I, and Z alpha1-antitrypsin and liver cirrhosis.
The association between Z alpha1-antitrypsin deficiency and juvenile cirrhosis is well-recognized, and there is now convincing evidence that the hepatic inclusions are the result of entangled polymers of mutant Z alpha1-antitrypsin. Four percent of the northern European Caucasian population are heterozygotes for the Z variant, but even more common is S alpha1-antitrypsin, which is found in up to 28% of southern Europeans. The S variant is known to have an increased susceptibility to polymerization, although this is marginal compared with the more conformationally unstable Z variant. There has been speculation that the two may interact to produce cirrhosis, but this has never been demonstrated experimentally. This hypothesis was raised again by the observation reported here of a mixed heterozygote for Z alpha1-antitrypsin and another conformationally unstable variant (I alpha1-antitrypsin; 39Arg-->Cys) identified in a 34-year-old man with cirrhosis related to alpha1-antitrypsin deficiency. The conformational stability of the I variant has been characterized, and we have used fluorescence resonance energy transfer to demonstrate the formation of heteropolymers between S and Z alpha1-antitrypsin. Taken together, these results indicate that not only may mixed variants form heteropolymers, but that this can causally lead to the development of cirrhosis.
Mahadeva
R
R
Respiratory Medicine Unit, Department of Medicine and Department of Haematology, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, United Kingdom. rm232@cam.ac.uk
Chang
W S
WS
Dafforn
T R
TR
Oakley
D J
DJ
Foreman
R C
RC
Calvin
J
J
Wight
D G
DG
Lomas
D A
DA
D000328:Adult; D000818:Animals; D006579:Heterozygote; D006801:Humans; D008103:Liver Cirrhosis / Q000235:genetics* / Q000473:pathology; D008297:Male; D008845:Microinjections; D008958:Models, Molecular; D009154:Mutation; D009865:Oocytes; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000235:genetics; D044465:White People; D014981:Xenopus; D000515:alpha 1-Antitrypsin / Q000737:chemistry*; D019896:alpha 1-Antitrypsin Deficiency / Q000235:genetics*
D012333:RNA, Messenger; D000515:alpha 1-Antitrypsin