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http://purl.uniprot.org/citations/30053538http://www.w3.org/1999/02/22-rdf-syntax-ns#typehttp://purl.uniprot.org/core/Journal_Citation
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Background

Calcium/calmodulin-dependent protein kinase kinase 2 (CaMKK2), a member of the Ca⁠2+/calmodulin-dependent kinase (CaMK) family, functions as an upstream activator of CaMKI, CaMKIV and AMP-activated protein kinase. Thus, CaMKK2 is involved in the regulation of several key physiological and pathophysiological processes. Previous studies have suggested that Ca2+/CaM binding may cause unique conformational changes in the CaMKKs compared with other CaMKs. However, the underlying mechanistic details remain unclear.

Methods

In this study, hydrogen-deuterium exchange coupled to mass spectrometry, time-resolved fluorescence spectroscopy, small-angle x-ray scattering and chemical cross-linking were used to characterize Ca2+/CaM binding-induced structural changes in CaMKK2.

Results

Our data suggest that: (i) the CaMKK2 kinase domain interacts with the autoinhibitory region (AID) through the N-terminal lobe of the kinase domain including the RP insert, a segment important for targeting downstream substrate kinases; (ii) Ca2+/CaM binding affects the structure of several regions surrounding the ATP-binding pocket, including the activation segment; (iii) although the CaMKK2:Ca2+/CaM complex shows high conformational flexibility, most of its molecules are rather compact; and (iv) AID-bound Ca2+/CaM transiently interacts with the CaMKK2 kinase domain.

Conclusions

Interactions between the CaMKK2 kinase domain and the AID differ from those of other CaMKs. In the absence of Ca2+/CaM binding the autoinhibitory region inhibits CaMKK2 by both blocking access to the RP insert and by affecting the structure of the ATP-binding pocket.

General significance

Our results corroborate the hypothesis that Ca2+/CaM binding causes unique conformational changes in the CaMKKs relative to other CaMKs."xsd:string
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http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/author"Herman P."xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/author"Obsil T."xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/author"Obsilova V."xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/author"Kylarova S."xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/author"Psenakova K."xsd:string
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http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/name"Biochim Biophys Acta Gen Subj"xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/pages"2304-2313"xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/title"CaMKK2 kinase domain interacts with the autoinhibitory region through the N-terminal lobe including the RP insert."xsd:string
http://purl.uniprot.org/citations/30053538http://purl.uniprot.org/core/volume"1862"xsd:string
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