NR AHSF
AU Mahadeva,R.; Dafforn,T.R.; Carrell,R.W.; Lomas,D.A.
TI 6-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerization. Implications for the prevention of Z alpha(1)-antitrypsin-related cirrhosis.
QU The Journal of Biological Chemistry 2002 Mar 1; 277(9): 6771-4
PT journal article
AB Conformational diseases such as amyloidosis, Alzheimer's disease, prion diseases, and the serpinopathies are all caused by structural rearrangements within a protein that transform it into a pathological species. These diseases are typified by the Z variant of alpha(1)-antitrypsin (E342K), which causes the retention of protein within hepatocytes as inclusion bodies that are associated with neonatal hepatitis and cirrhosis. The inclusion bodies result from the Z mutation perturbing the conformation of the protein, which facilitates a sequential interaction between the reactive center loop of one molecule and beta-sheet A of a second. Therapies to prevent liver disease must block this reactive loop-beta-sheet polymerization without interfering with other proteins of similar tertiary structure. We have used reactive loop peptides to explore the differences between the pathogenic Z and normal M alpha(1)-antitrypsin. The results show that the reactive loop is likely to be partially inserted into beta-sheet A in Z alpha(1)-antitrypsin. This conformational difference from M alpha(1)-antitrypsin was exploited with a 6-mer reactive loop peptide (FLEAIG) that selectively and stably bound Z alpha(1)-antitrypsin. The importance of this finding is that the peptide prevented the polymerization of Z alpha(1)-antitrypsin and did not significantly anneal to other proteins (such as antithrombin, alpha(1)-antichymotrypsin, and plasminogen activator inhibitor-1) with a similar tertiary structure. These findings provide a lead compound for the development of small molecule inhibitors that can be used to treat patients with Z alpha(1)-antitrypsin deficiency. Furthermore they demonstrate how a conformational disease process can be selectively inhibited with a small peptide.
MH Acrylamide/pharmacology; Electrophoresis, Polyacrylamide Gel; Endoplasmic Reticulum/metabolism; Human; Kinetics; Models, Molecular; Mutation; Peptides/chemistry; Protein Binding; Protein Conformation; Protein Structure, Secondary; Protein Structure, Tertiary; Serpins/*chemistry; Support, Non-U.S. Gov't; Time Factors; Urea/pharmacology; alpha 1-Antitrypsin/*chemistry; alpha 1-Antitrypsin Deficiency/*blood
AD Respiratory Medicine Unit, Department of Medicine, University of Cambridge, Cambridge CB2 2XY, United Kingdom. rm232@cam.ac.uk
SP englisch
PO USA