lnactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop: Implications for inhibitory function and conformational disease

摘要

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 con formational 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 strudure of a naturally occurring variant (Leu-55--Pro) of the plasma serpin α1-antichymotrypsin trapped as an inactive inter- mediate. The structure demonstrates a serpin configuration with partial insertion of the reactive loop into p-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 con formation 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 con formations, explains the loss of activity of plasma α1-antichymo- trypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55--Pro mutation.