[Frontiers in Bioscience 10, 288--299, January 1, 2005]

A PROTEIN FAMILY UNDER 'STRESS' - SERPIN STABILITY, FOLDING AND MISFOLDING

Glyn L. Devlin and Stephen P. Bottomley

Department of Biochemistry and Molecular Biology, Monash University, Wellington Road, Clayton, Victoria 3800, Australia

TABLE OF CONTENTS

1. Abstract
2. Introduction
3. The native serpin fold is a kinetically trapped intermediate
3.1. The molecular basis of serpin metastability
4. Low energy alternative serpin conformations
4.1. The latent conformation
4.2. The delta conformation
4.3. The polymeric conformations
4.3.1. Loop A-sheet polymers
4.3.2. Loop C-sheet polymers
4.3.3. Strand 7A polymers
4.3.4. Disulfide linked polymers
5. How do serpins attain a native fold and avoid misfolding?
6. The molecular switches of serpin misfolding
7. The kinetic pathway of serpin misfolding
7.1. The polymerogenic intermediate
8. Thriving under stress - the thermophilic serpins
9. The way forward
10. Acknowledgements
11. References

1. ABSTRACT

The native fold of inhibitory serpins (serpin proteinase inhibitors) is metastable and therefore does not represent the most stable conformation that the primary sequence encodes for. The most stable form is adopted when the reactive centre loop (RCL) inserts, as the fourth strand, into the A b -sheet. Currently a serpin can adopt at least four more stable conformations, termed the cleaved, delta, latent and polymeric states. The accessibility of these alternative low energy folds renders the serpin molecule susceptible to mutations that can result in dysfunction and pathology. Here, we discuss the means by which the serpin can attain and preserve this metastable conformation. We also consider the triggers for misfolding to these more stable states and the mechanisms by which it occurs.