Crystal structures of human CaMKIα reveal insights into the regulation mechanism of CaMKI

Manwu Zha; Chen Zhong; Ying Ou; Li Han; Jianchuan Wang; Jianping Ding

doi:10.1371/journal.pone.0044828

Crystal structures of human CaMKIα reveal insights into the regulation mechanism of CaMKI

PLoS One. 2012;7(9):e44828. doi: 10.1371/journal.pone.0044828. Epub 2012 Sep 20.

Authors

Manwu Zha¹, Chen Zhong, Ying Ou, Li Han, Jianchuan Wang, Jianping Ding

Affiliation

¹ State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.

Abstract

Human calcium/calmodulin-dependent protein kinase I (CaMKI) plays pivotal roles in the nervous system. The activity of human CaMKI is regulated by a regulatory region including an autoinhibitory segment and a CaM-binding segment. We report here four structures of three CaMKIα truncates in apo form and in complexes with ATP. In an apo, autoinhibited structure, the activation segment adopts a unique helical conformation which together with the autoinhibitory segment constrains helices αC and αD in inactive conformations, sequesters Thr177 from being phosphorylated, and occludes the substrate-binding site. In an ATP-bound, inactive structure, the activation segment is largely disordered and the CaM-binding segment protrudes out ready for CaM binding. In an ATP-bound, active structure, the regulatory region is dissociated from the catalytic core and the catalytic site assumes an active conformation. Detailed structural analyses reveal the interplay of the regulatory region, the activation segment, and the nucleotide-binding site in the regulation of CaMKI.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adenosine Triphosphate / metabolism
Amino Acid Sequence
Animals
Apoenzymes / antagonists & inhibitors
Apoenzymes / chemistry
Apoenzymes / genetics
Apoenzymes / metabolism
Calcium-Calmodulin-Dependent Protein Kinase Type 1 / antagonists & inhibitors
Calcium-Calmodulin-Dependent Protein Kinase Type 1 / chemistry*
Calcium-Calmodulin-Dependent Protein Kinase Type 1 / genetics
Calcium-Calmodulin-Dependent Protein Kinase Type 1 / metabolism*
Calmodulin / metabolism
Crystallography, X-Ray
Enzyme Activation
Humans
Models, Molecular
Molecular Sequence Data
Protein Structure, Secondary
Rats
Sequence Deletion

Substances

Apoenzymes
Calmodulin
Adenosine Triphosphate
Calcium-Calmodulin-Dependent Protein Kinase Type 1

Grants and funding

This work was supported by grants from the National Natural Science Foundation of China (30800171), the Ministry of Science and Technology of China (2011CB966301 and 2011CB911102), and the Science and Technology Commission of Shanghai Municipality (10JC1416500). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.