Switch #: SWTI000690

Switch type: Avidity-sensing

Description:
Phosphorylation of two 14-3-3-binding motifs in Foxo4 by PKB induces binding of 14-3-3 dimer. In the nucleus, this blocks binding to DNA, while in the cytoplasm it blocks reimport of Foxo4 into the nucleus by blocking its Nuclear Localisation Signal (NLS). Since binding of 14-3-3 to a single motif occurs with an affinity similar to the affinity of Foxo4 for DNA, multivalent binding of 14-3-3 dimer is required for efficient inhibition of DNA binding.

Participants:
(1) 14-3-3 protein zeta/delta (YWHAZ)
(2) Forkhead box protein O4 (FOXO4)

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 YWHAZ - YWHAZ

Interfaces
(1) 14-3-3 protein in 14-3-3 protein zeta/delta (YWHAZ)
(2) 14-3-3 protein _(3-236) in 14-3-3 protein zeta/delta (YWHAZ)

2Interaction #2 FOXO4 - Interaction #1 YWHAZ - YWHAZ

Requires Interaction #1 YWHAZ - YWHAZ

Interfaces
(3) LIG_14-3-3_1 motif (₂₉RSCTWP₃₄) in Forkhead box protein O4 (FOXO4)
(4) Interaction #1 YWHAZ - YWHAZ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₃₂ on Forkhead box protein O4 (FOXO4)) of the Forkhead box protein O4 (FOXO4) LIG_14-3-3_1 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₃₂: RAC-alpha serine/threonine-protein kinase (AKT1)

2Interaction #3 FOXO4 - Interaction #1 YWHAZ - YWHAZ

Requires Interaction #1 YWHAZ - YWHAZ

Interfaces
(5) LIG_14-3-3_2 motif (₁₉₃RRAASMD₁₉₉) in Forkhead box protein O4 (FOXO4)
(6) Interaction #1 YWHAZ - YWHAZ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₁₉₇ on Forkhead box protein O4 (FOXO4)) of the Forkhead box protein O4 (FOXO4) LIG_14-3-3_2 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₁₉₇: RAC-alpha serine/threonine-protein kinase (AKT1)

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₁₉₇ : PKB_group, RAC-alpha serine/threonine-protein kinase (AKT1).

(1) Two 14-3-3 binding motifs are required for stable association of Forkhead transcription factor FOXO4 with 14-3-3 proteins and inhibition of DNA binding.
Obsil et al. Biochemistry (2003)

(2) Regulation of nuclear translocation of forkhead transcription factor AFX by protein kinase B.
Takaishi et al. Proc. Natl. Acad. Sci. U.S.A. (1999)

Other switches involving participants
14-3-3 protein zeta/delta (YWHAZ) - 11 more (view)
Forkhead box protein O4 (FOXO4) - 1 more (view)

Other switches involving interfaces
14-3-3 protein - 38 more (view)
LIG_14-3-3_1 - 13 more (view)
LIG_14-3-3_2 - 7 more (view)