Switches.ELM

Switch #:

SWTI000525

Description:
CDK8/9 phosphorylates Mothers against decapentaplegic homolog 3 (SMAD3) at T179 and S208. Phosphorylation of T179 creates a binding site for the WW domain of Peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), while phosphorylation of S208 primes SMAD3 for phosphorylation of S204 by Glycogen synthase kinase-3 beta (GSK3B). The pS204-pS208 forms a binding site for the third WW domain of the E3 ubiquitin-protein ligase NEDD4-like (NEDD4L), whose second WW domain will displace the WW domain of PIN1 at the pT179-PY box site of SMAD3. This regulation couples SMAD3 activation to SMAD3 destruction in an ordered fashion. Dual phosphorylation of the two NEDD4L-binding sites mediates high-avidity binding of two WW domains of NEDD4L to SMAD3. See also switch details and switch details.

Participants:
(1) Mothers against decapentaplegic homolog 3 (SMAD3)
(2) E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interactions

Interaction #1 SMAD3 - NEDD4L

Interfaces
(1) LIG_WW_1 motif (₁₈₁PPGY₁₈₄) in Mothers against decapentaplegic homolog 3 (SMAD3)
(2) WW domain_(387-416) in E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of T₁₇₉ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) LIG_WW_1 motif - E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) WW domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: T₁₇₉: CDC2/CDKX subfamily

Additional Information
Affinity : T179: 60 µM, pT179: 8.5 µM, pT179-S204-pS208: 2.9 µM, pT179-pS204-pS208: 0.7 µM
Structural information: 2LB2

Interaction #2 SMAD3 - NEDD4L

Interfaces
(3) ELM:LIG_WW_Nedd4L motif (₂₀₃GSPNLSPN₂₁₀) in Mothers against decapentaplegic homolog 3 (SMAD3)
(4) WW domain_(499-528) in E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interaction Regulation
PTM-dependent Induction (Phosphorylation of S₂₀₄ and S₂₀₈ on Mothers against decapentaplegic homolog 3 (SMAD3)) of the Mothers against decapentaplegic homolog 3 (SMAD3) LIG_WW_Nedd4L motif - E3 ubiquitin-protein ligase NEDD4-like (NEDD4L) WW domain interaction

Regulatory Enzymes for switch
Modifying enzymes for residue: S₂₀₄: Glycogen synthase kinase-3 beta (GSK3B); S₂₀₈: CDC2/CDKX subfamily

Inferred Regulatory Enzymes for switch
Putative modifying enzymes for residue: S₂₀₄ : Cyclin-dependent kinase 4 (CDK4), Maternal embryonic leucine zipper kinase (Melk), Mitogen-activated protein kinase 1 (MAPK1). S₂₀₈ : Cyclin-dependent kinase 4 (CDK4), Cyclin-dependent kinase 8 (CDK8), Cyclin-dependent kinase 9 (CDK9), Mitogen-activated protein kinase 1 (MAPK1).

Additional Information
Affinity : T179: 60 µM, pT179: 8.5 µM, pT179-S204-pS208: 2.9 µM, pT179-pS204-pS208: 0.7 µM
Structural information: 2LAJ

Context

Switch pathways

References

(1) A Smad action turnover switch operated by WW domain readers of a phosphoserine code.
Aragón et al. Genes Dev. (2011)