Structural basis of membrane targeting by the Phox homology domain of cytokine-independent survival kinase (CISK-PX).
The cytokine-independent survival kinase (CISK) in the serum and glucocorticoid-regulated kinase family plays an important role in mediating cell growth and survival. N-terminal to its catalytic kinase domain, CISK contains a phox homology (PX) domain, a phosphoinositide-binding motif that directs the membrane localization of CISK and regulates CISK activity. We have determined the crystal structures of the mouse CISK-PX domain to unravel the structural basis of membrane targeting of CISK. In addition to the specific interactions conferred by the phosphoinositide-binding pocket, the structure suggests that a hydrophobic loop region and a hydrophilic beta-turn contribute to the interactions with the membrane. Furthermore, biochemical studies reveal that CISK-PX dimerizes in the presence of the linker between the PX domain and kinase domain, suggesting a multivalent mechanism in membrane localization of CISK.
Xing
Yi
Y
Department of Biological Structure, University of Washington, Seattle, Washington 98195-7420, USA.
Liu
Dan
D
Zhang
Rongguang
R
Joachimiak
Andrzej
A
Songyang
Zhou
Z
Xu
Wenqing
W
D020816:Amino Acid Motifs; D000818:Animals; D020134:Catalytic Domain; D002455:Cell Division; D002462:Cell Membrane / Q000378:metabolism*; D018360:Crystallography, X-Ray; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D018398:Homeodomain Proteins / Q000737:chemistry; D006801:Humans; D017874:Immediate-Early Proteins; D008027:Light; D051379:Mice; D008954:Models, Biological; D008958:Models, Molecular; D009154:Mutation; D009687:Nuclear Proteins; D010716:Phosphatidylinositols / Q000737:chemistry; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry* / Q000378:metabolism; D017433:Protein Structure, Secondary; D017434:Protein Structure, Tertiary; D012542:Scattering, Radiation; D000099184:Serum-Glucocorticoid Regulated Kinases
D018398:Homeodomain Proteins; D017874:Immediate-Early Proteins; D009687:Nuclear Proteins; D010716:Phosphatidylinositols; D017346:Protein Serine-Threonine Kinases; D000099184:Serum-Glucocorticoid Regulated Kinases; C082157:PRRX1 protein, human; C489936:Prrx1 protein, mouse