2f1x
From Proteopedia
(New page: 200px<br /> <applet load="2f1x" size="450" color="white" frame="true" align="right" spinBox="true" caption="2f1x, resolution 2.3Å" /> '''Crystal structure of...) |
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| - | [[Image:2f1x.gif|left|200px]]<br /> | + | [[Image:2f1x.gif|left|200px]]<br /><applet load="2f1x" size="350" color="white" frame="true" align="right" spinBox="true" |
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caption="2f1x, resolution 2.3Å" /> | caption="2f1x, resolution 2.3Å" /> | ||
'''Crystal structure of the TRAF-like domain of HAUSP/USP7 bound to a p53 peptide'''<br /> | '''Crystal structure of the TRAF-like domain of HAUSP/USP7 bound to a p53 peptide'''<br /> | ||
==Overview== | ==Overview== | ||
| - | Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as | + | Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), a deubiquitylating enzyme of the ubiquitin-specific processing protease family, specifically deubiquitylates both p53 and MDM2, hence playing an important yet enigmatic role in the p53-MDM2 pathway. Here we demonstrate that both p53 and MDM2 specifically recognize the N-terminal tumor necrosis factor-receptor associated factor (TRAF)-like domain of HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding elements were mapped to a peptide fragment in the carboxy-terminus of p53 and to a short-peptide region preceding the acidic domain of MDM2. The crystal structures of the HAUSP TRAF-like domain in complex with p53 and MDM2 peptides, determined at 2.3-A and 1.7-A resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP as that recognized by p53 but mediates more extensive interactions. Structural comparison led to the identification of a consensus peptide-recognition sequence by HAUSP. These results, together with the structure of a combined substrate-binding-and-deubiquitylation domain of HAUSP, provide important insights into regulation of the p53-MDM2 pathway by HAUSP. |
==Disease== | ==Disease== | ||
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==About this Structure== | ==About this Structure== | ||
| - | 2F1X 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:// | + | 2F1X 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=2F1X OCA]. |
==Reference== | ==Reference== | ||
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[[Category: Gu, L.]] | [[Category: Gu, L.]] | ||
[[Category: Hu, M.]] | [[Category: Hu, M.]] | ||
| - | [[Category: Jeffrey, P | + | [[Category: Jeffrey, P D.]] |
[[Category: Shi, Y.]] | [[Category: Shi, Y.]] | ||
[[Category: hausp]] | [[Category: hausp]] | ||
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[[Category: usp7]] | [[Category: usp7]] | ||
| - | ''Page seeded by [http:// | + | ''Page seeded by [http://oca.weizmann.ac.il/oca OCA ] on Thu Feb 21 17:16:50 2008'' |
Revision as of 15:16, 21 February 2008
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Crystal structure of the TRAF-like domain of HAUSP/USP7 bound to a p53 peptide
Contents |
Overview
Herpesvirus-associated ubiquitin-specific protease (HAUSP, also known as USP7), a deubiquitylating enzyme of the ubiquitin-specific processing protease family, specifically deubiquitylates both p53 and MDM2, hence playing an important yet enigmatic role in the p53-MDM2 pathway. Here we demonstrate that both p53 and MDM2 specifically recognize the N-terminal tumor necrosis factor-receptor associated factor (TRAF)-like domain of HAUSP in a mutually exclusive manner. HAUSP preferentially forms a stable HAUSP-MDM2 complex even in the presence of excess p53. The HAUSP-binding elements were mapped to a peptide fragment in the carboxy-terminus of p53 and to a short-peptide region preceding the acidic domain of MDM2. The crystal structures of the HAUSP TRAF-like domain in complex with p53 and MDM2 peptides, determined at 2.3-A and 1.7-A resolutions, respectively, reveal that the MDM2 peptide recognizes the same surface groove in HAUSP as that recognized by p53 but mediates more extensive interactions. Structural comparison led to the identification of a consensus peptide-recognition sequence by HAUSP. These results, together with the structure of a combined substrate-binding-and-deubiquitylation domain of HAUSP, provide important insights into regulation of the p53-MDM2 pathway by HAUSP.
Disease
Known diseases associated with this structure: Adrenal cortical carcinoma OMIM:[191170], Breast cancer OMIM:[191170], Colorectal cancer OMIM:[191170], Hepatocellular carcinoma OMIM:[191170], Histiocytoma OMIM:[191170], Li-Fraumeni syndrome OMIM:[191170], Multiple malignancy syndrome OMIM:[191170], Nasopharyngeal carcinoma OMIM:[191170], Osteosarcoma OMIM:[191170], Pancreatic cancer OMIM:[191170], Thyroid carcinoma OMIM:[191170]
About this Structure
2F1X is a Single protein structure of sequence from Homo sapiens. Full crystallographic information is available from OCA.
Reference
Structural basis of competitive recognition of p53 and MDM2 by HAUSP/USP7: implications for the regulation of the p53-MDM2 pathway., Hu M, Gu L, Li M, Jeffrey PD, Gu W, Shi Y, PLoS Biol. 2006 Feb;4(2):e27. Epub 2006 Jan 17. PMID:16402859
Page seeded by OCA on Thu Feb 21 17:16:50 2008
Categories: Homo sapiens | Single protein | Gu, L. | Hu, M. | Jeffrey, P D. | Shi, Y. | Hausp | P53 recognition | Peptide binding | Substrate recognition | Traf-like domain | Ubp | Usp7
