|
|
| (17 intermediate revisions not shown.) |
| Line 1: |
Line 1: |
| - | [[Image:1j8c.gif|left|200px]]<br /> | |
| - | <applet load="1j8c" size="450" color="white" frame="true" align="right" spinBox="true" | |
| - | caption="1j8c" /> | |
| - | '''Solution Structure of the Ubiquitin-like Domain of hPLIC-2'''<br /> | |
| | | | |
| - | ==Overview== | + | ==Solution Structure of the Ubiquitin-like Domain of hPLIC-2== |
| - | The 26S proteasome is essential for the proteolysis of proteins that have, been covalently modified by the attachment of polyubiquitinated chains., Although the 20S core particle performs the degradation, the 19S, regulatory cap complex is responsible for recognition of polyubiquitinated, substrates. We have focused on how the S5a component of the 19S complex, interacts with different ubiquitin-like (ubl) modules, to advance our, understanding of how polyubiquitinated proteins are targeted to the, proteasome. To achieve this, we have determined the solution structure of, the ubl domain of hPLIC-2 and obtained a structural model of hHR23a by, using NMR spectroscopy and homology modeling. We have also compared the, S5a binding properties of ubiquitin, SUMO-1, and the ubl domains of, hPLIC-2 and hHR23a and have identified the residues on their respective, S5a contact surfaces. We provide evidence that the S5a-binding surface on, the ubl domain of hPLIC-2 is required for its interaction with the, proteasome. This study provides structural insights into protein, recognition by the proteasome, and illustrates how the protein surface of, a commonly utilized fold has highly evolved for various biological roles. | + | <StructureSection load='1j8c' size='340' side='right'caption='[[1j8c]]' scene=''> |
| | + | == Structural highlights == |
| | + | <table><tr><td colspan='2'>[[1j8c]] is a 1 chain structure with sequence from [https://en.wikipedia.org/wiki/Homo_sapiens Homo sapiens]. Full experimental information is available from [http://oca.weizmann.ac.il/oca-bin/ocashort?id=1J8C OCA]. For a <b>guided tour on the structure components</b> use [https://proteopedia.org/fgij/fg.htm?mol=1J8C FirstGlance]. <br> |
| | + | </td></tr><tr id='method'><td class="sblockLbl"><b>[[Empirical_models|Method:]]</b></td><td class="sblockDat" id="methodDat">Solution NMR</td></tr> |
| | + | <tr id='resources'><td class="sblockLbl"><b>Resources:</b></td><td class="sblockDat"><span class='plainlinks'>[https://proteopedia.org/fgij/fg.htm?mol=1j8c FirstGlance], [http://oca.weizmann.ac.il/oca-bin/ocaids?id=1j8c OCA], [https://pdbe.org/1j8c PDBe], [https://www.rcsb.org/pdb/explore.do?structureId=1j8c RCSB], [https://www.ebi.ac.uk/pdbsum/1j8c PDBsum], [https://prosat.h-its.org/prosat/prosatexe?pdbcode=1j8c ProSAT]</span></td></tr> |
| | + | </table> |
| | + | == Disease == |
| | + | [https://www.uniprot.org/uniprot/UBQL2_HUMAN UBQL2_HUMAN] Defects in UBQLN2 are the cause of amyotrophic lateral sclerosis type 15 with or without frontotemporal dementia (ALS15) [MIM:[https://omim.org/entry/300857 300857]. A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia.<ref>PMID:21857683</ref> <ref>PMID:22892309</ref> <ref>PMID:22717235</ref> <ref>PMID:22560112</ref> |
| | + | == Function == |
| | + | [https://www.uniprot.org/uniprot/UBQL2_HUMAN UBQL2_HUMAN] Increases the half-life of proteins destined to be degraded by the proteasome; may modulate proteasome-mediated protein degradation.<ref>PMID:10983987</ref> |
| | + | == Evolutionary Conservation == |
| | + | [[Image:Consurf_key_small.gif|200px|right]] |
| | + | Check<jmol> |
| | + | <jmolCheckbox> |
| | + | <scriptWhenChecked>; select protein; define ~consurf_to_do selected; consurf_initial_scene = true; script "/wiki/ConSurf/j8/1j8c_consurf.spt"</scriptWhenChecked> |
| | + | <scriptWhenUnchecked>script /wiki/extensions/Proteopedia/spt/initialview01.spt</scriptWhenUnchecked> |
| | + | <text>to colour the structure by Evolutionary Conservation</text> |
| | + | </jmolCheckbox> |
| | + | </jmol>, as determined by [http://consurfdb.tau.ac.il/ ConSurfDB]. You may read the [[Conservation%2C_Evolutionary|explanation]] of the method and the full data available from [http://bental.tau.ac.il/new_ConSurfDB/main_output.php?pdb_ID=1j8c ConSurf]. |
| | + | <div style="clear:both"></div> |
| | + | <div style="background-color:#fffaf0;"> |
| | + | == Publication Abstract from PubMed == |
| | + | The 26S proteasome is essential for the proteolysis of proteins that have been covalently modified by the attachment of polyubiquitinated chains. Although the 20S core particle performs the degradation, the 19S regulatory cap complex is responsible for recognition of polyubiquitinated substrates. We have focused on how the S5a component of the 19S complex interacts with different ubiquitin-like (ubl) modules, to advance our understanding of how polyubiquitinated proteins are targeted to the proteasome. To achieve this, we have determined the solution structure of the ubl domain of hPLIC-2 and obtained a structural model of hHR23a by using NMR spectroscopy and homology modeling. We have also compared the S5a binding properties of ubiquitin, SUMO-1, and the ubl domains of hPLIC-2 and hHR23a and have identified the residues on their respective S5a contact surfaces. We provide evidence that the S5a-binding surface on the ubl domain of hPLIC-2 is required for its interaction with the proteasome. This study provides structural insights into protein recognition by the proteasome, and illustrates how the protein surface of a commonly utilized fold has highly evolved for various biological roles. |
| | | | |
| - | ==About this Structure==
| + | Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a.,Walters KJ, Kleijnen MF, Goh AM, Wagner G, Howley PM Biochemistry. 2002 Feb 12;41(6):1767-77. PMID:11827521<ref>PMID:11827521</ref> |
| - | 1J8C 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://ispc.weizmann.ac.il/oca-bin/ocashort?id=1J8C OCA].
| + | |
| | | | |
| - | ==Reference==
| + | From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.<br> |
| - | Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a., Walters KJ, Kleijnen MF, Goh AM, Wagner G, Howley PM, Biochemistry. 2002 Feb 12;41(6):1767-77. PMID:[http://ispc.weizmann.ac.il//pmbin/getpm?pmid=11827521 11827521]
| + | </div> |
| | + | <div class="pdbe-citations 1j8c" style="background-color:#fffaf0;"></div> |
| | + | == References == |
| | + | <references/> |
| | + | __TOC__ |
| | + | </StructureSection> |
| | [[Category: Homo sapiens]] | | [[Category: Homo sapiens]] |
| - | [[Category: Single protein]] | + | [[Category: Large Structures]] |
| - | [[Category: Goh, A.M.]] | + | [[Category: Goh AM]] |
| - | [[Category: Howley, P.M.]] | + | [[Category: Howley PM]] |
| - | [[Category: Kleijnen, M.F.]] | + | [[Category: Kleijnen MF]] |
| - | [[Category: Wagner, G.]] | + | [[Category: Wagner G]] |
| - | [[Category: Walters, K.J.]] | + | [[Category: Walters KJ]] |
| - | [[Category: ubiquitin-like domain]]
| + | |
| - | | + | |
| - | ''Page seeded by [http://ispc.weizmann.ac.il/oca OCA ] on Mon Nov 12 17:38:14 2007''
| + | |
| Structural highlights
Disease
UBQL2_HUMAN Defects in UBQLN2 are the cause of amyotrophic lateral sclerosis type 15 with or without frontotemporal dementia (ALS15) [MIM:300857. A neurodegenerative disorder affecting upper motor neurons in the brain and lower motor neurons in the brain stem and spinal cord, resulting in fatal paralysis. Sensory abnormalities are absent. The pathologic hallmarks of the disease include pallor of the corticospinal tract due to loss of motor neurons, presence of ubiquitin-positive inclusions within surviving motor neurons, and deposition of pathologic aggregates. The etiology of amyotrophic lateral sclerosis is likely to be multifactorial, involving both genetic and environmental factors. The disease is inherited in 5-10% of the cases. Patients with ALS15 may develop frontotemporal dementia.[1] [2] [3] [4]
Function
UBQL2_HUMAN Increases the half-life of proteins destined to be degraded by the proteasome; may modulate proteasome-mediated protein degradation.[5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
Publication Abstract from PubMed
The 26S proteasome is essential for the proteolysis of proteins that have been covalently modified by the attachment of polyubiquitinated chains. Although the 20S core particle performs the degradation, the 19S regulatory cap complex is responsible for recognition of polyubiquitinated substrates. We have focused on how the S5a component of the 19S complex interacts with different ubiquitin-like (ubl) modules, to advance our understanding of how polyubiquitinated proteins are targeted to the proteasome. To achieve this, we have determined the solution structure of the ubl domain of hPLIC-2 and obtained a structural model of hHR23a by using NMR spectroscopy and homology modeling. We have also compared the S5a binding properties of ubiquitin, SUMO-1, and the ubl domains of hPLIC-2 and hHR23a and have identified the residues on their respective S5a contact surfaces. We provide evidence that the S5a-binding surface on the ubl domain of hPLIC-2 is required for its interaction with the proteasome. This study provides structural insights into protein recognition by the proteasome, and illustrates how the protein surface of a commonly utilized fold has highly evolved for various biological roles.
Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a.,Walters KJ, Kleijnen MF, Goh AM, Wagner G, Howley PM Biochemistry. 2002 Feb 12;41(6):1767-77. PMID:11827521[6]
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
References
- ↑ Deng HX, Chen W, Hong ST, Boycott KM, Gorrie GH, Siddique N, Yang Y, Fecto F, Shi Y, Zhai H, Jiang H, Hirano M, Rampersaud E, Jansen GH, Donkervoort S, Bigio EH, Brooks BR, Ajroud K, Sufit RL, Haines JL, Mugnaini E, Pericak-Vance MA, Siddique T. Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia. Nature. 2011 Aug 21;477(7363):211-5. doi: 10.1038/nature10353. PMID:21857683 doi:10.1038/nature10353
- ↑ Synofzik M, Maetzler W, Grehl T, Prudlo J, Vom Hagen JM, Haack T, Rebassoo P, Munz M, Schols L, Biskup S. Screening in ALS and FTD patients reveals 3 novel UBQLN2 mutations outside the PXX domain and a pure FTD phenotype. Neurobiol Aging. 2012 Dec;33(12):2949.e13-7. doi:, 10.1016/j.neurobiolaging.2012.07.002. Epub 2012 Aug 11. PMID:22892309 doi:10.1016/j.neurobiolaging.2012.07.002
- ↑ Williams KL, Warraich ST, Yang S, Solski JA, Fernando R, Rouleau GA, Nicholson GA, Blair IP. UBQLN2/ubiquilin 2 mutation and pathology in familial amyotrophic lateral sclerosis. Neurobiol Aging. 2012 Oct;33(10):2527.e3-10. doi:, 10.1016/j.neurobiolaging.2012.05.008. Epub 2012 Jun 19. PMID:22717235 doi:10.1016/j.neurobiolaging.2012.05.008
- ↑ Daoud H, Suhail H, Szuto A, Camu W, Salachas F, Meininger V, Bouchard JP, Dupre N, Dion PA, Rouleau GA. UBQLN2 mutations are rare in French and French-Canadian amyotrophic lateral sclerosis. Neurobiol Aging. 2012 Sep;33(9):2230.e1-2230.e5. doi:, 10.1016/j.neurobiolaging.2012.03.015. Epub 2012 May 3. PMID:22560112 doi:10.1016/j.neurobiolaging.2012.03.015
- ↑ Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM. The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome. Mol Cell. 2000 Aug;6(2):409-19. PMID:10983987
- ↑ Walters KJ, Kleijnen MF, Goh AM, Wagner G, Howley PM. Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a. Biochemistry. 2002 Feb 12;41(6):1767-77. PMID:11827521
|
