2KXQ

Solution Structure of Smurf2 WW2 and WW3 bound to Smad7 PY motif containing peptide

Summary for 2KXQ

• Entry DOI: 10.2210/pdb2kxq/pdb
• NMR Information: BMRB: 16923
• Descriptor: E3 ubiquitin-protein ligase SMURF2, Smad7 PY motif containing peptide (2 entities in total)
• Functional Keywords: ww, py motif, smurf2, tgf-beta, modular binding, protein binding
• Biological source: Homo sapiens (human); More
• Cellular location: Nucleus: Q9HAU4
• Total number of polymer chains: 2
• Total formula weight: 12304.42

Authors

Chong, A.,Lin, H.,Wrana, J.,Forman-Kay, J.D. (deposition date: 2010-05-11, release date: 2010-10-13, Last modification date: 2024-05-01)

Primary citation

Chong, P.A.,Lin, H.,Wrana, J.L.,Forman-Kay, J.D.
Coupling of tandem Smad ubiquitination regulatory factor (Smurf) WW domains modulates target specificity.
Proc.Natl.Acad.Sci.USA, 107:18404-18409, 2010

PubMed Abstract: Smad ubiquitination regulatory factor 2 (Smurf2) is an E3 ubiquitin ligase that participates in degradation of TGF-β receptors and other targets. Smurf2 WW domains recognize PPXY (PY) motifs on ubiquitin ligase target proteins or on adapters, such as Smad7, that bind to E3 target proteins. We previously demonstrated that the isolated WW3 domain of Smurf2, but not the WW2 domain, can directly bind to a Smad7 PY motif. We show here that the WW2 augments this interaction by binding to the WW3 and making auxiliary contacts with the PY motif and a novel E/D-S/T-P motif, which is N-terminal to all Smad PY motifs. The WW2 likely enhances the selectivity of Smurf2 for the Smad proteins. NMR titrations confirm that Smad1 and Smad2 are bound by Smurf2 with the same coupled WW domain arrangement used to bind Smad7. The analogous WW domains in the short isoform of Smurf1 recognize the Smad7 PY peptide using the same coupled mechanism. However, a longer Smurf1 isoform, which has an additional 26 residues in the inter-WW domain linker, is only partially able to use the coupled WW domain binding mechanism. The longer linker results in a decrease in affinity for the Smad7 peptide. Interdomain coupling of WW domains enhances selectivity and enables the tuning of interactions by isoform switching.

PubMed: 20937913
DOI: 10.1073/pnas.1003023107

Experimental method

SOLUTION NMR