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.
Highlights
Intracellular calcium is an important secondary messenger, of which the concentration ranges from a basal value of about 50 nM to stimulated levels of 1–10 mM in response to signals such as growth factors and neurotransmitters [1]
The overall conformation is similar, detailed analyses of these structures reveal their distinctive features in the activation segment, the nucleotide-binding site, and the regulatory region, which together provide new insights into the regulation mechanism of calmodulin-dependent protein kinase I (CaMKI)
The structural data are in consistency with the previous biochemical and structural data including the unresponsiveness of the inactive CaMKI to CaMK kinase (CaMKK) [26], the constitutive albeit relatively low activity of CaMKI297 [15], and the adoption of a helical conformation of the CaM-binding segment for CaM binding [27]
Summary
Intracellular calcium is an important secondary messenger, of which the concentration ranges from a basal value of about 50 nM to stimulated levels of 1–10 mM in response to signals such as growth factors and neurotransmitters [1]. CaM binds to and stimulates the activities of a family of Ca2+/CaMdependent serine/threonine protein kinases (CaMKs), thereby regulating their functions. CaMKI plays pivotal roles in the nervous system It is critical for long-term potentiation via activation of ERK [3] and recruitment of synaptic Ca2+-permeable AMPARs [4]. It promotes dendritic arborization [5], neurite outgrowth [6], and formation of spines, synapses and axons in hippocampal neurons [7,8]. The kinase recognizes a consensus sequence Hyd-X-Arg-X-X-Ser/Thr-X-X-X-Hyd, in which Hyd is a hydrophobic residue [10], and its substrates include the synaptic vesicle-associated proteins, namely synapsin 1 and 2 [11], the cAMP response element-binding protein (CREB) [12], and the recently identified target glial cell missing 1 (GCM1) [13]
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