Switch #: SWTI000294

Switch type: Specificity

Switch subtype: Altered binding specificity

Description:
Phosphorylation of G1/S-specific cyclin-E1 (CCNE1) at S399 generates a docking site for Glycogen synthase kinase-3 beta (GSK3B). Subsequent phosphorylation of CCNE1 by Glycogen synthase kinase-3 beta (GSK3B) at T395 switches the specificity of CCNE1 to the F-box/WD repeat-containing protein 7 (FBXW7), which recruits CCNE1 to the SCF ubiquitin ligase complex to mark CCNE1 for degradation.

Participants:
(1) G1/S-specific cyclin-E1 (CCNE1)
(2) Glycogen synthase kinase-3 beta (GSK3B)
(3) F-box/WD repeat-containing protein 7 (FBXW7)

This is a sequential switch. The interactions in this switch take place in a defined order. The order is defined by numbers to the left of each interaction. More than one interaction can occur in each step, these interactions occur independently but are necessary for future step

1Interaction #1 CCNE1 - GSK3B

Is mutually exclusive with Interaction #2 CCNE1 - FBXW7

Interfaces
(1) MOD_GSK3_1 motif (₃₉₂GLLTPPQS₃₉₉) in G1/S-specific cyclin-E1 (CCNE1)
(2) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₃₉₉ on G1/S-specific cyclin-E1 (CCNE1)) of the G1/S-specific cyclin-E1 (CCNE1) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₃₉₉: Cyclin-dependent kinase 2 (CDK2)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₃₉₉ : Cyclin-dependent kinase 2 (CDK2).

2Interaction #2 CCNE1 - FBXW7

Requires Interaction #1 CCNE1 - GSK3B
Is mutually exclusive with Interaction #1 CCNE1 - GSK3B

Interfaces
(3) DEG_SCF_FBW7_1 motif (₃₉₃LLTPPQS₃₉₉) in G1/S-specific cyclin-E1 (CCNE1)
(4) WD domain, G-beta repeat _(371-407) and _(411-447) and _(451-487) and _(491-527) and _(531-567) and _(571-607) and _(611-650) in F-box/WD repeat-containing protein 7 (FBXW7)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₃₉₅ and S₃₉₉ on G1/S-specific cyclin-E1 (CCNE1)) of the G1/S-specific cyclin-E1 (CCNE1) DEG_SCF_FBW7_1 motif - F-box/WD repeat-containing protein 7 (FBXW7) WD domain, G-beta repeat interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₃₉₅: Glycogen synthase kinase-3 beta (GSK3B); S₃₉₉: Cyclin-dependent kinase 2 (CDK2)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₃₉₅ : Cyclin-dependent kinase 2 (CDK2), Glycogen synthase kinase-3 alpha (GSK3A), Glycogen synthase kinase-3 beta (GSK3B). S₃₉₉ : Cyclin-dependent kinase 2 (CDK2).

Additional Information
Structural information: 2OVQ

(1) Multisite phosphorylation by Cdk2 and GSK3 controls cyclin E degradation.
Welcker et al. Mol. Cell (2003)

(2) Structure of a Fbw7-Skp1-cyclin E complex: multisite-phosphorylated substrate recognition by SCF ubiquitin ligases.
Hao et al. Mol. Cell (2007)

Other switches involving participants
Glycogen synthase kinase-3 beta (GSK3B) - 18 more (view)
G1/S-specific cyclin-E1 (CCNE1) - 2 more (view)
F-box/WD repeat-containing protein 7 (FBXW7) - 8 more (view)

Other switches involving interfaces
Protein kinase domain - 35 more (view)
MOD_GSK3_1 - 18 more (view)
WD domain, G-beta repeat - 36 more (view)
DEG_SCF_FBW7_1 - 4 more (view)