Switch #: SWTI000284

Switch type: Specificity

Switch subtype: Altered binding specificity

Description:
Phosphorylation of T238 of MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) by Cyclin-dependent kinase 1 (CDK1) primes for phosphorylation of T234 by Glycogen synthase kinase-3 beta (GSK3B), which primes for phosphorylation of S230 by GSK3B. Triple-phosphorylated hNIFK (MKI67IP) binds strongly to Antigen KI-67 (MKI67).

Participants:
(1) MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)
(2) Cyclin-dependent kinase 1 (CDK1)
(3) Glycogen synthase kinase-3 beta (GSK3B)
(4) Antigen KI-67 (MKI67)

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 MKI67IP - CDK1

Interfaces
(1) ELM:MOD_CDK motif (₂₃₅PVCTPTF₂₄₁) in MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)
(2) Protein kinase domain _(4-287) in Cyclin-dependent kinase 1 (CDK1)

2Interaction #2 MKI67IP - GSK3B

Requires Interaction #1 MKI67IP - CDK1

Interfaces
(3) MOD_GSK3_1 motif (₂₃₁QGPTPVCT₂₃₈) in MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)
(4) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₂₃₈ on MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)) of the MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₂₃₈: Cyclin-dependent kinase 1 (CDK1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₂₃₈ : Cyclin-dependent kinase 1 (CDK1).

3Interaction #3 MKI67IP - GSK3B

Requires Interaction #2 MKI67IP - GSK3B

Interfaces
(5) MOD_GSK3_1 motif (₂₂₇TVDSQGPT₂₃₄) in MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)
(6) Protein kinase domain _(56-340) in Glycogen synthase kinase-3 beta (GSK3B)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₂₃₄ on MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)) of the MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) MOD_GSK3_1 motif - Glycogen synthase kinase-3 beta (GSK3B) Protein kinase domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₂₃₄: Glycogen synthase kinase-3 beta (GSK3B)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: T₂₃₄ : Glycogen synthase kinase-3 alpha (GSK3A), Glycogen synthase kinase-3 beta (GSK3B).

4Interaction #4 MKI67IP - MKI67

Interfaces
(7) LIG_FHA_2 motif (₂₃₈TPTFLER₂₄₄) in MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)
(8) FHA domain _(27-91) in Antigen KI-67 (MKI67)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₃₀, T₂₃₄ and T₂₃₈ on MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP)) of the MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) LIG_FHA_2 motif - Antigen KI-67 (MKI67) FHA domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₃₀: Glycogen synthase kinase-3 beta (GSK3B); T₂₃₄: Glycogen synthase kinase-3 beta (GSK3B); T₂₃₈: Cyclin-dependent kinase 1 (CDK1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₂₃₀ : Glycogen synthase kinase-3 alpha (GSK3A), Glycogen synthase kinase-3 beta (GSK3B). T₂₃₄ : Glycogen synthase kinase-3 alpha (GSK3A), Glycogen synthase kinase-3 beta (GSK3B). T₂₃₈ : Cyclin-dependent kinase 1 (CDK1).

Additional Information
Affinity : S230-T234-T238: 109 µM, S230-T234-pT238: 131 µM, S230-pT234-pT238: 0.17 µM, pS230-pT234-pT238: 0.077 µM
Structural information: 2AFF

(1) Sequential phosphorylation and multisite interactions characterize specific target recognition by the FHA domain of Ki67.
Byeon et al. Nat. Struct. Mol. Biol. (2005)

Other switches involving participants
Glycogen synthase kinase-3 beta (GSK3B) - 18 more (view)
MKI67 FHA domain-interacting nucleolar phosphoprotein (MKI67IP) - 1 more (view)
Antigen KI-67 (MKI67) - 1 more (view)
Cyclin-dependent kinase 1 (CDK1) - 1 more (view)

Other switches involving interfaces
Protein kinase domain - 35 more (view)
FHA domain - 11 more (view)
MOD_GSK3_1 - 18 more (view)
LIG_FHA_2 - 9 more (view)