2JY7

NMR structure of the ubiquitin associated (UBA) domain of p62 (SQSTM1). RDC refined

Summary for 2JY7

• Entry DOI: 10.2210/pdb2jy7/pdb
• Related: 2JY8
• NMR Information: BMRB: 15591
• Descriptor: Ubiquitin-binding protein p62 (1 entity in total)
• Functional Keywords: ubiquitin binding, ubiquitin associated domain, helical bundle, three helices, alternative splicing, apoptosis, cytoplasm, differentiation, disease mutation, endosome, immune response, metal-binding, nucleus, phosphoprotein, polymorphism, zinc, zinc-finger, protein binding
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 1
• Total formula weight: 5744.41

Authors

Long, J.E.,Layfield, R.,Searle, M.S. (deposition date: 2007-12-07, release date: 2007-12-18, Last modification date: 2024-05-01)

Primary citation

Long, J.,Gallagher, T.R.,Cavey, J.R.,Sheppard, P.W.,Ralston, S.H.,Layfield, R.,Searle, M.S.
Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch
J.Biol.Chem., 283:5427-5440, 2008

PubMed Abstract: The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-kappaB and is an important regulator of osteoclastogenesis. Mutations affecting the receptor activator of NF-kappaB signaling axis can result in human skeletal disorders, including those identified in the C-terminal ubiquitin-associated (UBA) domain of p62 in patients with Paget disease of bone. These observations suggest that the disease may involve a common mechanism related to alterations in the ubiquitin-binding properties of p62. The structural basis for ubiquitin recognition by the UBA domain of p62 has been investigated using NMR and reveals a novel binding mechanism involving a slow exchange structural reorganization of the UBA domain to a "bound" non-canonical UBA conformation that is not significantly populated in the absence of ubiquitin. The repacking of the three-helix bundle generates a binding surface localized around the conserved Xaa-Gly-Phe-Xaa loop that appears to optimize both hydrophobic and electrostatic surface complementarity with ubiquitin. NMR titration analysis shows that the p62-UBA binds to Lys 48-linked di-ubiquitin with approximately 4-fold lower affinity than to mono-ubiquitin, suggesting preferential binding of the p62-UBA to single ubiquitin units, consistent with the apparent in vivo preference of the p62 protein for Lys 63-linked polyubiquitin chains (which adopt a more open and extended structure). The conformational switch observed on binding may represent a novel mechanism that underlies specificity in regulating signalinduced protein recognition events.

PubMed: 18083707
DOI: 10.1074/jbc.M704973200

Experimental method

SOLUTION NMR