期刊
JOURNAL OF MOLECULAR BIOLOGY
卷 415, 期 2, 页码 307-317出版社
ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD
DOI: 10.1016/j.jmb.2011.11.008
关键词
intrinsically disordered protein; folding; phosphatase
资金
- National Science Foundation [MCB-0843551]
- Kentucky Science and Engineering Foundation [KSEF-148-502-08-227]
- University of Kansas
- National Institutes of Health National Center for Research Resources [P20 RR020171]
- Direct For Biological Sciences [0843551] Funding Source: National Science Foundation
- Div Of Molecular and Cellular Bioscience [0843551] Funding Source: National Science Foundation
The highly conserved phosphatase calcineurin (CaN) plays vital roles in numerous processes including T-cell activation, development and function of the central nervous system, and cardiac growth. It is activated by the calcium sensor calmodulin (CaM). CaM binds to a regulatory domain (RD) within CaN, causing a conformational change that displaces an auto-inhibitory domain (AID) from the active site, resulting in activation of the phosphatase. This is the same general mechanism by which CaM activates CaM-dependent protein kinases. Previously published data have hinted that the RD of CaN is intrinsically disordered. In this work, we demonstrate that the RD is unstructured and that it folds upon binding CaM, ousting the AID from the catalytic site. The RD is 95 residues long, with the AID attached to its C-terminal end and the 24-residue CaM binding region toward the N-terminal end. This is unlike the CaM-dependent protein kinases that have CaM binding sites and AIDs immediately adjacent in sequence. Our data demonstrate that not only does the CaM binding region folds but also an similar to 25- to 30-residue region between it and the AID folds, resulting in over half of the RD adopting a-helical structure. This appears to be the first observation of CaM inducing folding of this scale outside of its binding site on a target protein. (C) 2011 Elsevier Ltd. All rights reserved.
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