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NMR structural studies of the ItchWW3 domain reveal that phosphorylation at T30 inhibits the interaction with PPxY-containing ligands.

Morales B, Ramirez-Espain X, Shaw AZ, Martin-Malpartida P, Yraola F, Sánchez-Tilló E, Farrera C, Celada A, Royo M, Macias MJ
Structure 15 473-83 (2007)
Cited: 21 times
EuropePMC logo PMID: 17437719

Abstract

In this work, we study the role of phosphorylation as a regulatory mechanism for the interaction between the E3 ubiquitin ligase ItchWW3 domain and two PPxY motifs of one of its targets, the Epstein-Barr virus latent membrane protein 2A. Whereas ligand phosphorylation only diminishes binding, domain phosphorylation at residue T30 abrogates it. We show that two ItchWW domains can be phosphorylated at this position, using CK2 and PKA kinases and/or with stimulated T lymphocyte lysates. To better understand the regulation process, we determined the NMR structures of the ItchWW3-PPxY complex and of the phosphoT30-ItchWW3 variant. The peptide binds the domain using both XP and tyrosine grooves. A hydrogen bond from T30 to the ligand is also detected. This hydrogen-bond formation is precluded in the variant, explaining the inhibition upon phosphorylation. Our results suggest that phosphorylation at position 30 in ItchWW domains can be a mechanism to inhibit target recognition in vivo.

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  1. A survey of the year 2007 literature on applications of isothermal titration calorimetry. Bjelić S, Jelesarov I. J Mol Recognit 21 289-312 (2008)
  2. ITCH as a potential therapeutic target in human cancers. Yin Q, Wyatt CJ, Han T, Smalley KSM, Wan L. Semin Cancer Biol 67 117-130 (2020)
  3. Regulation of Ubiquitin Enzymes in the TGF-β Pathway. Iyengar PV. Int J Mol Sci 18 E877 (2017)

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  1. Structural basis for the versatile interactions of Smad7 with regulator WW domains in TGF-β Pathways. Aragón E, Goerner N, Xi Q, Gomes T, Gao S, Massagué J, Macias MJ. Structure 20 1726-1736 (2012)
  2. Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity. Chong PA, Lin H, Wrana JL, Forman-Kay JD. Proc Natl Acad Sci U S A 107 18404-18409 (2010)
  3. WW domains of the yes-kinase-associated-protein (YAP) transcriptional regulator behave as independent units with different binding preferences for PPxY motif-containing ligands. Iglesias-Bexiga M, Castillo F, Cobos ES, Oka T, Sudol M, Luque I. PLoS One 10 e0113828 (2015)
  4. TGIF1 homeodomain interacts with Smad MH1 domain and represses TGF-β signaling. Guca E, Suñol D, Ruiz L, Konkol A, Cordero J, Torner C, Aragon E, Martin-Malpartida P, Riera A, Macias MJ. Nucleic Acids Res 46 9220-9235 (2018)
  5. Interfacial water molecules in SH3 interactions: a revised paradigm for polyproline recognition. Martin-Garcia JM, Ruiz-Sanz J, Luque I. Biochem J 442 443-451 (2012)
  6. Molecular basis of the binding of YAP transcriptional regulator to the ErbB4 receptor tyrosine kinase. Schuchardt BJ, Bhat V, Mikles DC, McDonald CB, Sudol M, Farooq A. Biochimie 101 192-202 (2014)
  7. Structural characterization of a new binding motif and a novel binding mode in group 2 WW domains. Ramirez-Espain X, Ruiz L, Martin-Malpartida P, Oschkinat H, Macias MJ. J Mol Biol 373 1255-1268 (2007)
  8. Phosphorylation of a conserved Thr357 in yeast Nedd4-like ubiquitin ligase Rsp5 is involved in down-regulation of the general amino acid permease Gap1. Sasaki T, Takagi H. Genes Cells 18 459-475 (2013)
  9. Ligand binding to WW tandem domains of YAP2 transcriptional regulator is under negative cooperativity. Schuchardt BJ, Mikles DC, Hoang LM, Bhat V, McDonald CB, Sudol M, Farooq A. FEBS J 281 5532-5551 (2014)
  10. Binding site plasticity in viral PPxY Late domain recognition by the third WW domain of human NEDD4. Iglesias-Bexiga M, Palencia A, Corbi-Verge C, Martin-Malpartida P, Blanco FJ, Macias MJ, Cobos ES, Luque I. Sci Rep 9 15076 (2019)
  11. Structure-based design of a Cortistatin analogue with immunomodulatory activity in models of inflammatory bowel disease. Rol Á, Todorovski T, Martin-Malpartida P, Escolà A, Gonzalez-Rey E, Aragón E, Verdaguer X, Vallès-Miret M, Farrera-Sinfreu J, Puig E, Fernández-Carneado J, Ponsati B, Delgado M, Riera A, Macias MJ. Nat Commun 12 1869 (2021)
  12. Cooperative and selective roles of the WW domains of the yeast Nedd4-like ubiquitin ligase Rsp5 in the recognition of the arrestin-like adaptors Bul1 and Bul2. Watanabe D, Murai H, Tanahashi R, Nakamura K, Sasaki T, Takagi H. Biochem Biophys Res Commun 463 76-81 (2015)
  13. Unveiling the dimer/monomer propensities of Smad MH1-DNA complexes. Ruiz L, Kaczmarska Z, Gomes T, Aragon E, Torner C, Freier R, Baginski B, Martin-Malpartida P, de Martin Garrido N, Marquez JA, Cordeiro TN, Pluta R, Macias MJ. Comput Struct Biotechnol J 19 632-646 (2021)


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