2jy7
From Proteopedia
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caption="2jy7" /> | caption="2jy7" /> | ||
'''NMR structure of the ubiquitin associated (UBA) domain of p62 (SQSTM1). RDC refined'''<br /> | '''NMR structure of the ubiquitin associated (UBA) domain of p62 (SQSTM1). RDC refined'''<br /> | ||
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| + | ==Overview== | ||
| + | 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. | ||
==About this Structure== | ==About this Structure== | ||
2JY7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JY7 OCA]. | 2JY7 is a [http://en.wikipedia.org/wiki/Single_protein Single protein] structure of sequence from [http://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full crystallographic information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=2JY7 OCA]. | ||
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| + | ==Reference== | ||
| + | Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch., Long J, Gallagher TR, Cavey JR, Sheppard PW, Ralston SH, Layfield R, Searle MS, J Biol Chem. 2008 Feb 29;283(9):5427-5440. Epub 2007 Dec 14. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=18083707 18083707] | ||
[[Category: Homo sapiens]] | [[Category: Homo sapiens]] | ||
[[Category: Single protein]] | [[Category: Single protein]] | ||
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[[Category: polymorphism]] | [[Category: polymorphism]] | ||
[[Category: protein binding]] | [[Category: protein binding]] | ||
| - | [[Category: three | + | [[Category: three helice]] |
[[Category: ubiquitin associated domain]] | [[Category: ubiquitin associated domain]] | ||
[[Category: ubiquitin binding]] | [[Category: ubiquitin binding]] | ||
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[[Category: zinc-finger]] | [[Category: zinc-finger]] | ||
| - | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Fri Mar 14 09:42:55 2008'' |
Revision as of 07:42, 14 March 2008
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NMR structure of the ubiquitin associated (UBA) domain of p62 (SQSTM1). RDC refined
Overview
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.
About this Structure
2JY7 is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Ubiquitin Recognition by the Ubiquitin-associated Domain of p62 Involves a Novel Conformational Switch., Long J, Gallagher TR, Cavey JR, Sheppard PW, Ralston SH, Layfield R, Searle MS, J Biol Chem. 2008 Feb 29;283(9):5427-5440. Epub 2007 Dec 14. PMID:18083707
Page seeded by OCA on Fri Mar 14 09:42:55 2008
Categories: Homo sapiens | Single protein | Layfield, R. | Long, J E. | Searle, M S. | Alternative splicing | Apoptosis | Cytoplasm | Differentiation | Disease mutation | Endosome | Helical bundle | Immune response | Metal-binding | Nucleus | Phosphoprotein | Polymorphism | Protein binding | Three helice | Ubiquitin associated domain | Ubiquitin binding | Zinc | Zinc-finger
