Abstract
The adipokine vaspin (serpinA12) is mainly expressed in white adipose tissue and exhibits various beneficial effects on obesity-related processes. Kallikrein 7 is the only known target protease of vaspin and is inhibited by the classical serpin inhibitory mechanism involving a cleavage of the reactive center loop between P1 (M378) and P1′ (E379). Here, we present the X-ray structure of vaspin, cleaved between M378 and E379. We provide a comprehensive analysis of differences between the uncleaved and cleaved forms in the shutter, breach, and hinge regions with relation to common molecular features underlying the serpin inhibitory mode. Furthermore, we point out differences towards other serpins and provide novel data underlining the remarkable stability of vaspin. We speculate that the previously reported FKGx1Wx2x3 motif in the breach region may play a decisive role in determining the reactive center loop configuration in the native vaspin state and might contribute to the high thermostability of vaspin. Thus, this structure may provide a basis for future mutational studies.
Acknowledgments
The vaspin expression plasmid was kindly provided by Dr. J. Wada (Department of Medicine and Clinical Science Okayama University Graduate School of Medicine, Okayama, Japan). We thank Susanne Moschuetz and Antje Keim for help with purification and crystallization. This work was supported by the European Union and the Free State of Saxony (J.T.H.) and by the Deutsche Forschungsgemeinschaft SFB1052 ‘Obesity Mechanisms’ (C4 N.S., C7 J.T.H.). The authors thank the Joint Berlin MX-Laboratory at BESSY II, Berlin, Germany, for beam time and assistance during synchrotron data collection as well as the Helmholtz Zentrum Berlin for travelling support.
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