Switch #:
SWTI000525
Switch type:
Avidity-sensing

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 localisation
ELM curated: cytosol, integral membrane protein, integral plasma membrane protein
Inferred: cytosol, nucleoplasm


Switch pathways
Inferred: Endocytosis
References

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




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