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Papers In Press, published online ahead of print December 28, 2001
Medicine, University of Cambridge, Cambridge CB2 2XY
Corresponding Author: rm232{at}cam.ac.uk
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 species (Carrell RW & Lomas DA (1997) Lancet 350;134-8). 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, juvenile cirrhosis and hepatocellular carcinoma. The inclusion bodies result from the Z mutation perturbing the conformation of the protein which facilitates a sequential interaction between the reactive centre loop of one molecule and beta-sheet A of a second. Therapies to prevent liver disease must block this reactive loop-beta-sheet polymerisation 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 polymerisation 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.
J. Biol. Chem, 10.1074/jbc.C100722200
Submitted on December 10, 2001
Revised on December 23, 2001
Accepted on December 28, 2001
Six-mer peptide selectively anneals to a pathogenic serpin conformation and blocks polymerisation: Implications for the prevention of Z alpha-1 antitrypsin related cirrhosis
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