Structures of apicomplexan calcium-dependent protein kinases reveal mechanism of activation by calcium.
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.
Wernimont
Amy K
AK
Structural Genomics Consortium, University of Toronto, Toronto, Ontario, Canada.
Artz
Jennifer D
JD
Finerty
Patrick
P
Lin
Yu-Hui
YH
Amani
Mehrnaz
M
Allali-Hassani
Abdellah
A
Senisterra
Guillermo
G
Vedadi
Masoud
M
Tempel
Wolfram
W
Mackenzie
Farrell
F
Chau
Irene
I
Lourido
Sebastian
S
Sibley
L David
LD
Hui
Raymond
R
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
D002118:Calcium; D011494:Protein Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases