Table 1.

Structural and functional observations and potential roles of CMGC-kinase residues

Residue	Location	Comments	Reference
Residues in ERK2 characteristic of CMGC kinases
Y185	Activation loop	Second phosphorylation site	Canagarajah et al. 1997
V186	Activation loop	Upon activation packs up against the HRD arginine	See text
R189	APE region	P-2i-arginine: hydrogen bonds to substrate binding loop and to second activation loop phosphate moiety	Canagarajah et al. 1997; Brown et al. 1999; Dajani et al. 2001
W190	APE region	P-3i-aromatic: in Cdk2 interacts with substrate P-3 position	Brown et al. 1999
R192	APE region; P+1 binding pocket	The CMGC-arginine: hydrogen bonds to the carbonyl oxygen of the conformationally strained residue (A187) and interacts with phosphorylated tyrosine (Y186)	Brown et al. 1999; Canagarajah et al. 1997
L198	APE region	Mutation of this residue to alanine in ERK2 disrupt substrate binding	Lee et al. 2004
Y203	APE region	Stabilizes the backbone of the phosphorylated threonine (T160)	Johnson et al. 1996
1207	αF helix	Packs up against Y203	See text
C214	αF helix	Potentially critical interaction with kinase-shared W210
A217	αF helix	Packing interaction with L225
L225	αF-to-αG loop	Mediates a CH-pi interaction with kinase conserved F226
P227, G228	αF-to-αG region	Involved in hydrogen bonding interactions with the CMGC-glutamine and with peptide substrate	See text
Q234	αF-to-αG region	CMGC-glutamine: hydrogen bonds to the backbone atoms linked to substrate binding	See text
L242, G243	CMGC-insert	Possible structural roles related to the CMGC-insert.	See text
Resident characteristic of individual families
F181Erk2	Activation loop	May mediate interaction with CMGC-insert upon kinase deactivation	See text
Y231Erk2	N terminus of αG	Possible second phosphorylated tyrosine that could interact with CMGC-arginine; mutation of this residue disrupts substrate binding	See text; Lee et al. 2004
G43Cdk2	Loop connecting to αC	Provides flexibility in the PSTAIRE helix; hydrogen bonds to a cyclin A lysine that is subject to a strong cyclin A-specific constraint.	Russo et al. 1996
	Helix (PSTAIRE)		See text
P45Cdk2	N terminus of αC	Cyclin binding and C-helix conformation	Russo et al. 1996
T47Cdk2	Helix (PSTAIRE)
W227Cdk2	CMGC-insert	Packing of the CMGC-insert against the kinase C-terminal domain	See text
P228Cdk2
Q89-N95Gsk2	Loop before αC helix	Immediately before an arginine (R96) that hydrogen bonds with the activation loop first phosphorylation site	See text
C178Gsk2	Catalytic loop	The side-chain sulfur packs against conserved hydrogen bonds between the HRD-backbone and a kinase-shared aspartate	See text
K205Gsk	Activation loop	Potential interaction with preprimed substrate phosphorylation site	Dajani et al. 2001
C218Gsk	P+1 binding pocket	Corresponds to strained position interacting with CMGC-arginine
N553Sky1p	Activation loop	Could potentially interact with the P+1 residue in the substrate	(Fig. 5e ▶)
Q566Sky1p	P+1 binding pocket	Corresponds to strained position interacting with CMGC-arginine	See text
P606Sky1p	αF-to-αG region	Occurs just before or within the Sky1p-specific insert
H618Sky1p	αF-to-αG region	Replaces the CMGC-glutamine (Q234ERK2)	See text
C289Dyrk	Catalytic loop	Potential disulphide bond with C312 in the activation loop	See text
C312Dyrk	Activation loop	Potential disulphide bond with C289
Y319Dyrk	Activation loop	First phosphorylation site (normally threonine)	Becker and Joost 1999
Q323Dyrk	P+1 binding pocket	Corresponds to strained position interacting with CMGC-arginine	See text
W176Ck2	Activation loop	Packs against the C-helix
E180Ck2	Activation loop	Hydrogen bonds to an N-terminal CK2-specific tyrosine	Niefind et al. 2001
K198Ck2	P+1 binding pocket	Replaces the CMGC-arginine	See text
G199Ck2	APE region	Replaces the APE alanine
L213Ck2	AF helix	Displaces the buried water typically found in protein kinases	See text