Switches.ELM

Switch #:

SWTI000526

Switch type:
Cumulative

Switch subtype:
Rheostatic

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. Phosphorylation of S208 in SMAD3 induces binding of the third WW domain of NEDD4L, while additional phosphorylation of S204 in SMAD3 further increases the affinity of this interaction. 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) ELM:LIG_WW_Nedd4L motif (₂₀₃GSPNLSPN₂₁₀) in Mothers against decapentaplegic homolog 3 (SMAD3)
(2) WW domain_(499-528) in E3 ubiquitin-protein ligase NEDD4-like (NEDD4L)

Interaction Regulation
PTM-dependent Enhancement (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 localisation

Switch pathways

References

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