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Serpins - structure, function and disease

Background:

Serpins are an important family of proteinase inhibitors present in higher eukaryotes. Numerous human serpins have been implicated in disease processes such as heart disease, cancer, liver cirrhosis and emphysema. Serpins are able to undergo a massive conformational rearrangement (see figure), which is essential for their mechanism of inhibition. Many disease-linked mutations in serpins occur in regions of the molecule central to the conformational change and result in instability and polymerisation.

Selected references:

J.A. Irving, R.N. Pike, A.M. Lesk, and J.C. Whisstock. "Phylogeny of the Serpin Superfamily: Implications of patterns of amino acids conservation for structure and function". Genome Res. 12: 1845-1864 (2000).

J.C. Whisstock, R. Skinner, R.C. Carrell and A.M. Lesk. "An Atlas of Serpin Conformations". Trends Biochem. Sci., 23, 63-67, (1998).

G.A. Silverman, P.I. Bird, R.W. Carrell, F.C. Church, P.B. Coughlin, P. Gettins, J. Irving, D.A. Lomas, R.W. Moyer, P. Pemberton, W. Remold O'Donnell, G. Salvesen, J. Travis and J.C. Whisstock. "The serpins are an expanding superfamily of structurally similar but functionally diverse proteins." J. Biol. Chem., accepted for publication.

A wide variety of projects focusing upon the serpin structure and function are available including:

Project 1 The structure and molecular mechanism of the serpin MENT (in collaboration with Dr Rob Pike): MENT is a DNA binding serpin that condenses chromatin to inert heterochromatin. This project aims to elucidate the molecular mechanism of this unique function. In particular, mutants of MENT will be constructed, expressed and purified and tested for their ability to interact with proteinase and DNA.

Project 2 Mechanism of serpin inhibition of cysteine proteinases: whilst the mechanism of serine proteinase inhibition by serpins is relatively well understood, the mechanism by which serpins inhibit cysteine proteinases remains to be characterised and is the focus of this investigation.

Project 3 Understanding the role of conserved residues in the stability and folding of the serpin antitrypsin (In collaboration with Dr Steve Bottomley): A sequence alignment of all known serpins enabled identification of highly conserved positions in the serpin structure. This project will focus upon understanding the role of clusters of conserved residues in serpin conformational change.

Project 4 Identifying serpins in primitive organisms such as corals and jellyfish (in collaboration with Dr Phil Bird): Serpins have been identified in higher plants and animals. However, we are yet to discover a serpin-like molecule in fungi or prokaryotes. This project will attempt to identify serpins in cnidarian organisms such as jellyfish. In particular, identification of a primitive serpin is expected to shed light on the evolution and original proteinase target of this important family of proteinase inhibitors.