Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 283, Issue 9, Pages 5427-5440Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M704973200
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Funding
- Arthritis Research UK Funding Source: Medline
- Biotechnology and Biological Sciences Research Council Funding Source: Medline
- Medical Research Council Funding Source: Medline
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The p62 protein functions as a scaffold in signaling pathways that lead to activation of NF-kappa B and is an important regulator of osteoclastogenesis. Mutations affecting the receptor activator of NF-kappa B 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 similar to 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 signal-induced protein recognition events.
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