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    Inactive conformation of the serpin alpha 1-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease

    Gooptu, Bibek and Hazes, B. and Chang, W.-S.W. and Dafforn, T.R. and Carrell, R.W. and Read, R.J. and Lomas, D.A. (2000) Inactive conformation of the serpin alpha 1-antichymotrypsin indicates two-stage insertion of the reactive loop: implications for inhibitory function and conformational disease. Proceedings of the National Academy of Sciences of the United States of America 97 (1), pp. 67-72. ISSN 0027-8424.

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    Abstract

    The serpins are a family of proteinase inhibitors that play a central role in the control of proteolytic cascades. Their inhibitory mechanism depends on the intramolecular insertion of the reactive loop into β-sheet A after cleavage by the target proteinase. Point mutations within the protein can allow aberrant conformational transitions characterized by β-strand exchange between the reactive loop of one molecule and β-sheet A of another. These loop-sheet polymers result in diseases as varied as cirrhosis, emphysema, angio-oedema, and thrombosis, and we recently have shown that they underlie an early-onset dementia. We report here the biochemical characteristics and crystal structure of a naturally occurring variant (Leu-55–Pro) of the plasma serpin α1-antichymotrypsin trapped as an inactive intermediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into β-sheet A. The lower part of the sheet is filled by the last turn of F-helix and the loop that links it to s3A. This conformation matches that of proposed intermediates on the pathway to complex and polymer formation in the serpins. In particular, this intermediate, along with the latent and polymerized conformations, explains the loss of activity of plasma α1-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55–Pro mutation.

    Metadata

    Item Type: Article
    School: Birkbeck Schools and Departments > School of Science > Biological Sciences
    Research Centre: Structural Molecular Biology, Institute of (ISMB)
    Depositing User: Administrator
    Date Deposited: 24 Jun 2015 14:47
    Last Modified: 06 Dec 2016 10:42
    URI: http://eprints.bbk.ac.uk/id/eprint/12439

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