Hypersensitive mousetraps, alpha1-antitrypsin deficiency and dementia.
Alpha(1)-antitrypsin functions as a "mousetrap" to inhibit its target proteinase, neutrophil elastase. The common severe Z deficiency variant (Glu(342)-->Lys) destabilizes the mousetrap to allow a sequential protein-protein interaction between the reactive-centre loop of one molecule and beta-sheet A of another. These loop-sheet polymers 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. Loop-sheet polymerization is now recognized to underlie deficiency variants of other members of the serine proteinase inhibitor (serpin) superfamily, i.e. antithrombin, C1 esterase inhibitor and alpha(1)-antichymotrypsin, which are associated with thrombosis, angio-oedema and emphysema respectively. Moreover, we have shown recently that the same process in a neuron-specific protein, neuroserpin, underlies a novel inclusion-body dementia, known as familial encephalopathy with neuroserpin inclusion bodies. Our understanding of the structural basis of polymerization has allowed the development of strategies to prevent the aberrant protein-protein interaction in vitro. This must now be achieved in vivo if we are to treat the associated clinical syndromes.
Lomas
D A
DA
Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge Institute for Medical Research, Wellcome Trust/MRC Building, Hills Road, Cambridge CB2 2XY, U.K. dal16@cam.ac.uk
Lourbakos
A
A
Cumming
S A
SA
Belorgey
D
D
D000799:Angioedema / Q000209:etiology; D001704:Biopolymers / Q000737:chemistry; D003704:Dementia / Q000188:drug therapy / Q000209:etiology* / Q000235:genetics / Q000378:metabolism; D004646:Emphysema / Q000209:etiology; D014644:Genetic Variation; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D011487:Protein Conformation; D015843:Serpins / Q000737:chemistry / Q000235:genetics; D013927:Thrombosis / Q000209:etiology; D000515:alpha 1-Antitrypsin / Q000737:chemistry / Q000235:genetics; D019896:alpha 1-Antitrypsin Deficiency / Q000150:complications* / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D001704:Biopolymers; D015843:Serpins; D000515:alpha 1-Antitrypsin