NMR Characterization of Long-Range Order in Intrinsically Disordered Proteins
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- 作者：Loc Salmon ; Gabrielle Nodet ; Valry Ozenne ; Guowei Yin ; Malene Ringkjø ; bing Jensen ; Markus Zweckstetter ; Martin Blackledge
- 刊名：Journal of the American Chemical Society
- 出版年：2010
- 出版时间：June 23, 2010
- 年：2010
- 卷：132
- 期：24
- 页码：8407-8418
- 全文大小：727K
- 年卷期：v.132,no.24(June 23, 2010)
- ISSN：1520-5126
文摘
Intrinsically disordered proteins (IDPs) are predicted to represent a significant fraction of the human genome, and the development of meaningful molecular descriptions of these proteins remains a key challenge for contemporary structural biology. In order to describe the conformational behavior of IDPs, a molecular representation of the disordered state based on diverse sources of structural data that often exhibit complex and very different averaging behavior is required. In this study, we propose a combination of paramagnetic relaxation enhancements (PREs) and residual dipolar couplings (RDCs) to define both long-range and local structural features of IDPs in solution. We demonstrate that ASTEROIDS, an ensemble selection algorithm, faithfully reproduces intramolecular contacts, even in the presence of highly diffuse, ill-defined target interactions. We also show that explicit modeling of spin-label mobility significantly improves the reproduction of experimental PRE data, even in the case of highly disordered proteins. Prediction of the effects of transient long-range contacts on RDC profiles reveals that weak intramolecular interactions can induce a severe distortion of the profiles that compromises the description of local conformational sampling if it is not correctly taken into account. We have developed a solution to this problem that involves efficiently combining RDC and PRE data to simultaneously determine long-range and local structure in highly flexible proteins. This combined analysis is shown to be essential for the accurate interpretation of experimental data from α-synuclein, an important IDP involved in human neurodegenerative disease, confirming the presence of long-range order between distant regions in the protein.