TY - JOUR
T1 - Inactive conformation of the serpin α1-antichymotrypsin indicates two-stage insertion of the reactive loop
T2 - Implications for inhibitory function and conformational disease
AU - Gooptu, Bibekbrata
AU - Hazes, B.
AU - Chang, W.-S.W.
AU - Dafforn, T.R.
AU - Carrell, R.W.
AU - Read, R.J.
AU - Lomas, D.A.
N1 - Copyright 2004 Elsevier Science B.V., Amsterdam. All rights reserved.
PY - 2000/1/4
Y1 - 2000/1/4
N2 - 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 α-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 α-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.
AB - 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 α-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 α-antichymotrypsin associated with chronic obstructive pulmonary disease in patients with the Leu-55-Pro mutation.
UR - http://www.scopus.com/inward/record.url?partnerID=yv4JPVwI&eid=2-s2.0-0034602778&md5=df030e1c8a2e3ae015e39172bff8f227
U2 - 10.1073/pnas.97.1.67
DO - 10.1073/pnas.97.1.67
M3 - Article
AN - SCOPUS:0034602778
SN - 0027-8424
VL - 97
SP - 67
EP - 72
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 1
ER -