| 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
[ADRM1_HUMAN] Functions as a proteasomal ubiquitin receptor. Recruits the deubiquitinating enzyme UCHL5 at the 26S proteasome and promotes its activity.[5] [6] [7] [8] [9] [UBQL2_HUMAN] Increases the half-life of proteins destined to be degraded by the proteasome; may modulate proteasome-mediated protein degradation.[10]
Publication Abstract from PubMed
Three receptors (Rpn1/S2/PSMD2, Rpn10/S5a, Rpn13/Adrm1) in the proteasome bind substrates by interacting with conjugated ubiquitin chains and/or shuttle factors (Rad23/HR23, Dsk2/PLIC/ubiquilin, Ddi1) that carry ubiquitinated substrates to proteasomes. We solved the structure of two such receptors with their preferred shuttle factor, namely hRpn13Pru:hPLIC2UBL and scRpn1 T1:scRad23UBL. We find that ubiquitin folds in Rad23 and Dsk2 are fine-tuned by residue substitutions to achieve high affinity for Rpn1 and Rpn13, respectively. A single substitution in hPLIC2 yields enhanced interactions with the Rpn13 ubiquitin contact surface and sterically blocks hRpn13 binding to its preferred ubiquitin chain type, K48-linked chains. Rpn1 T1 binds two ubiquitins in tandem and we find that Rad23 binds exclusively to the higher-affinity Helix28/Helix30 site. Rad23 contacts at Helix28/Helix30 are optimized compared to ubiquitin by multiple conservative amino acid substitutions. Thus, shuttle factors deliver substrates to proteasomes through fine-tuned ubiquitin-like surfaces.
Structures of Rpn1 T1:Rad23 and hRpn13:hPLIC2 Reveal Distinct Binding Mechanisms between Substrate Receptors and Shuttle Factors of the Proteasome.,Chen X, Randles L, Shi K, Tarasov SG, Aihara H, Walters KJ Structure. 2016 Jul 6. pii: S0969-2126(16)30125-3. doi:, 10.1016/j.str.2016.05.018. PMID:27396824[11]
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
- ↑ Hamazaki J, Iemura S, Natsume T, Yashiroda H, Tanaka K, Murata S. A novel proteasome interacting protein recruits the deubiquitinating enzyme UCH37 to 26S proteasomes. EMBO J. 2006 Oct 4;25(19):4524-36. Epub 2006 Sep 21. PMID:16990800 doi:http://dx.doi.org/10.1038/sj.emboj.7601338
- ↑ Qiu XB, Ouyang SY, Li CJ, Miao S, Wang L, Goldberg AL. hRpn13/ADRM1/GP110 is a novel proteasome subunit that binds the deubiquitinating enzyme, UCH37. EMBO J. 2006 Dec 13;25(24):5742-53. Epub 2006 Nov 30. PMID:17139257 doi:http://dx.doi.org/7601450
- ↑ Jorgensen JP, Lauridsen AM, Kristensen P, Dissing K, Johnsen AH, Hendil KB, Hartmann-Petersen R. Adrm1, a putative cell adhesion regulating protein, is a novel proteasome-associated factor. J Mol Biol. 2006 Jul 28;360(5):1043-52. Epub 2006 Jun 21. PMID:16815440 doi:http://dx.doi.org/S0022-2836(06)00703-0
- ↑ Yao T, Song L, Xu W, DeMartino GN, Florens L, Swanson SK, Washburn MP, Conaway RC, Conaway JW, Cohen RE. Proteasome recruitment and activation of the Uch37 deubiquitinating enzyme by Adrm1. Nat Cell Biol. 2006 Sep;8(9):994-1002. Epub 2006 Aug 13. PMID:16906146 doi:ncb1460
- ↑ Husnjak K, Elsasser S, Zhang N, Chen X, Randles L, Shi Y, Hofmann K, Walters KJ, Finley D, Dikic I. Proteasome subunit Rpn13 is a novel ubiquitin receptor. Nature. 2008 May 22;453(7194):481-8. PMID:18497817 doi:10.1038/nature06926
- ↑ 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
- ↑ Chen X, Randles L, Shi K, Tarasov SG, Aihara H, Walters KJ. Structures of Rpn1 T1:Rad23 and hRpn13:hPLIC2 Reveal Distinct Binding Mechanisms between Substrate Receptors and Shuttle Factors of the Proteasome. Structure. 2016 Jul 6. pii: S0969-2126(16)30125-3. doi:, 10.1016/j.str.2016.05.018. PMID:27396824 doi:http://dx.doi.org/10.1016/j.str.2016.05.018
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