Switch #: SWTI000354

Switch type: Avidity-sensing

Description:
Phosphorylation of two 14-3-3-binding motifs in RAF proto-oncogene serine/threonine-protein kinase (RAF1) in response to growth factors induces high-avidity binding to dimeric 14-3-3 protein zeta/delta (YWHAZ), with pS621 being the high-affinity interaction site. This interaction locks RAF proto-oncogene serine/threonine-protein kinase (RAF1) in an inhibited conformation.

Participants:
(1) 14-3-3 protein zeta/delta (YWHAZ)
(2) RAF proto-oncogene serine/threonine-protein kinase (RAF1)

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 RAF1 - Interaction #1 YWHAZ - YWHAZ

Requires Interaction #1 YWHAZ - YWHAZ

Interfaces
(3) LIG_14-3-3_1 motif (₂₅₆RSTSTP₂₆₁) in RAF proto-oncogene serine/threonine-protein kinase (RAF1)
(4) Interaction #1 YWHAZ - YWHAZ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₅₉ on RAF proto-oncogene serine/threonine-protein kinase (RAF1)) of the RAF proto-oncogene serine/threonine-protein kinase (RAF1) LIG_14-3-3_1 motif - 14-3-3 protein interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₅₉: RAC-alpha serine/threonine-protein kinase (AKT1)

2Interaction #3 RAF1 - Interaction #1 YWHAZ - YWHAZ

Requires Interaction #1 YWHAZ - YWHAZ

Interfaces
(5) LIG_14-3-3_1 motif (₆₁₈RSASEP₆₂₃) in RAF proto-oncogene serine/threonine-protein kinase (RAF1)
(6) Interaction #1 YWHAZ - YWHAZ

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₆₂₁ on RAF proto-oncogene serine/threonine-protein kinase (RAF1)) of the RAF proto-oncogene serine/threonine-protein kinase (RAF1) LIG_14-3-3_1 motif - 14-3-3 protein interaction

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₆₂₁ : PKA_group, 5'-AMP-activated protein kinase catalytic subunit alpha-1 (Prkaa1), cAMP-dependent protein kinase catalytic subunit alpha (Prkaca), cAMP-dependent protein kinase catalytic subunit alpha (PRKACA), RAF proto-oncogene serine/threonine-protein kinase (RAF1).

(1) Dynamic changes in C-Raf phosphorylation and 14-3-3 protein binding in response to growth factor stimulation: differential roles of 14-3-3 protein binding sites.
Hekman et al. J. Biol. Chem. (2004)

(2) Phosphorylation and regulation of Raf by Akt (protein kinase B).
Zimmermann et al. Science (1999)