title: Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium.
abstract: Calcium-dependent protein kinases (CDPKs) have pivotal roles in the calcium-signaling pathway in plants, ciliates and apicomplexan parasites and comprise a calmodulin-dependent kinase (CaMK)-like kinase domain regulated by a calcium-binding domain in the C terminus. To understand this intramolecular mechanism of activation, we solved the structures of the autoinhibited (apo) and activated (calcium-bound) conformations of CDPKs from the apicomplexan parasites Toxoplasma gondii and Cryptosporidium parvum. In the apo form, the C-terminal CDPK activation domain (CAD) resembles a calmodulin protein with an unexpected long helix in the N terminus that inhibits the kinase domain in the same manner as CaMKII. Calcium binding triggers the reorganization of the CAD into a highly intricate fold, leading to its relocation around the base of the kinase domain to a site remote from the substrate binding site. This large conformational change constitutes a distinct mechanism in calcium signal-transduction pathways.
authors.affiliation: Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Amy K
authors.initials: AK
authors.lastname: Wernimont
authors.forename: Jennifer D
authors.initials: JD
authors.lastname: Artz
authors.forename: Patrick
authors.initials: P
authors.lastname: Finerty
authors.forename: Yu-Hui
authors.initials: YH
authors.lastname: Lin
authors.forename: Mehrnaz
authors.initials: M
authors.lastname: Amani
authors.forename: Abdellah
authors.initials: A
authors.lastname: Allali-Hassani
authors.forename: Guillermo
authors.initials: G
authors.lastname: Senisterra
authors.forename: Masoud
authors.initials: M
authors.lastname: Vedadi
authors.forename: Wolfram
authors.initials: W
authors.lastname: Tempel
authors.forename: Farrell
authors.initials: F
authors.lastname: Mackenzie
authors.forename: Irene
authors.initials: I
authors.lastname: Chau
authors.forename: Sebastian
authors.initials: S
authors.lastname: Lourido
authors.forename: L David
authors.initials: LD
authors.lastname: Sibley
authors.forename: Raymond
authors.initials: R
authors.lastname: Hui
mesh_terms: D002118:Calcium / Q000737:chemistry / Q000378:metabolism*; D016785:Cryptosporidium parvum / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004789:Enzyme Activation; D008958:Models, Molecular; D011485:Protein Binding; D011487:Protein Conformation; D011494:Protein Kinases / Q000737:chemistry* / Q000378:metabolism*; D014122:Toxoplasma / Q000201:enzymology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases
chemical_list: D002118:Calcium; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases