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J. Biol. Chem., Vol. 282, Issue 37, 26802-26809, September 14, 2007

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Aeropin from the Extremophile Pyrobaculum aerophilum Bypasses the Serpin Misfolding Trap^*

Lisa D. Cabrita¹², James A. Irving¹³, Mary C. Pearce, James C. Whisstock⁴, and Stephen P. Bottomley⁵

From the Department of Biochemistry and Molecular Biology, Monash University, Victoria 3800, Australia and ARC Centre of Excellence for Structural and Function Microbial Genomics, Monash University, Clayton 3800, Australia

Serpins are metastable proteinase inhibitors. Serpin metastability drives both a large conformational change that is utilized during proteinase inhibition and confers an inherent structural flexibility that renders serpins susceptible to aggregation under certain conditions. These include point mutations (the basis of a number of important human genetic diseases), small changes in pH, and an increase in temperature. Many studies of serpins from mesophilic organisms have highlighted an inverse relationship: mutations that confer a marked increase in serpin stability compromise inhibitory activity. Here we present the first biophysical characterization of a metastable serpin from a hyperthermophilic organism. Aeropin, from the archaeon Pyrobaculum aerophilum, is both highly stable and an efficient proteinase inhibitor. We also demonstrate that because of high kinetic barriers, aeropin does not readily form the partially unfolded precursor to serpin aggregation. We conclude that stability and activity are not mutually exclusive properties in the context of the serpin fold, and propose that the increased stability of aeropin is caused by an unfolding pathway that minimizes the formation of an aggregation-prone intermediate ensemble, thereby enabling aeropin to bypass the misfolding fate observed with other serpins.

Received for publication, June 19, 2007 , and in revised form, July 9, 2007.

^* This work was supported by the Australian Research Council and the NHMRC. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ National Health and Medical Research Council Australia (NHMRC) CJ Martin Fellows. These authors contributed equally to this work.

² Present address: Dept. of Chemistry, Cambridge University, Cambridge CB2 1EW, UK.

³ Present address: Dept. of Structural Biology, Wellcome Trust Centre for Human Genetics, Oxford University, Oxford OX3 7BN, UK.

⁵ A Senior Research Fellow of the NHMRC. To whom correspondence may be addressed. Tel.: 61399053703; Fax: 6199054699; E-mail: steve.bottomley{at}med.monash.edu.au.

⁴ A Principal Research Fellow of the NHMRC and a Monash University Senior Logan Fellow. To whom correspondence may be addressed. Tel.: 61399053747; Fax:6199053726; E-mail: james.whisstock{at}med.monash.edu.au.

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