title: Crystal structures of human CaMKIα reveal insights into the regulation mechanism of CaMKI.
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.
authors.affiliation: State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Manwu
authors.initials: M
authors.lastname: Zha
authors.forename: Chen
authors.initials: C
authors.lastname: Zhong
authors.forename: Ying
authors.initials: Y
authors.lastname: Ou
authors.forename: Li
authors.initials: L
authors.lastname: Han
authors.forename: Jianchuan
authors.initials: J
authors.lastname: Wang
authors.forename: Jianping
authors.initials: J
authors.lastname: Ding
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D001051:Apoenzymes / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1 / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D002147:Calmodulin / Q000378:metabolism; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D017433:Protein Structure, Secondary; D051381:Rats; D017384:Sequence Deletion
chemical_list: D001051:Apoenzymes; D002147:Calmodulin; D000255:Adenosine Triphosphate; D054729:Calcium-Calmodulin-Dependent Protein Kinase Type 1