Journal article

Identification and Characterization of a Misfolded Monomeric Serpin Formed at Physiological Temperature

MC Pearce, GA Powers, SC Feil, G Hansen, MW Parker, SP Bottomley



The native serpin state is kinetically trapped. However, under mildly destabilizing conditions, the conformational landscape changes, and a number of nonnative conformations with increased stability can be readily formed. The ability to undergo structural change is due to intrinsic strain within the serpin's tertiary fold, which is utilized for proteinase inhibition but renders the protein susceptible to aberrant folding and self-association. The relationship between these various conformations is poorly understood. Antichymotrypsin (ACT) is an inhibitory serpin that readily forms a number of inactive conformations, induced via either environmental stress or interaction with proteinases. Her..

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Awarded by National Cancer Institute

Awarded by National Institute of General Medical Science

Funding Acknowledgements

This work was supported by the Australian Synchrotron Research Program, which is funded by the Commonwealth of Australia under the Major National Research Facilities Program. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Energy Research. GM/CA CAT has been funded, in whole or in part, with US Federal funds from the National Cancer Institute (Y1-CO-1020) and the National Institute of General Medical Science (Y1-GM-1104). S.C.F. was supported by a National Health and Medical Research Council of Australia (NHMRC) Industry Fellowship. M.W.P. is an Australian Research Council Federation Fellow and NHMRC Honorary Fellow. S.P.B. is an NHMRC Research Fellow. This work was supported, in part, by a program grant from the NHMRC. We would like to thank Dr. J. Huntington for providing the model structures for the intermediate and polymer structures seen in Fig. 1. We would also like to thank Dr. S. McGowan for critical appraisal of the manuscript.