UBQLN2

UBQLN2
Available structures
PDB	Ortholog search: PDBe RCSB
List of PDB id codes
	1J8C
Identifiers
Aliases	UBQLN2 , ALS15, CHAP1, DSK2, N4BP4, PLIC2, HRIHFB2157, ubiquilin 2
External IDs	OMIM: 300264 MGI: 1860283 HomoloGene: 81830 GeneCards: UBQLN2
Gene location (Human)
Chr.	X chromosome (human)
End	56,567,868 bp
Gene location (Mouse)
Chr.	X chromosome (mouse)
End	152,284,566 bp
RNA expression pattern
	Top expressed in
	cerebellar vermis; ; pons; ; postcentral gyrus; ; endothelial cell; ; Brodmann area 23; ; retinal pigment epithelium; ; entorhinal cortex; ; superior vestibular nucleus; ; seminal vesicula; ; middle temporal gyrus;
	Top expressed in
	habenula; ; ventral tegmental area; ; arcuate nucleus; ; median eminence; ; subiculum; ; seminal vesicula; ; paraventricular nucleus of hypothalamus; ; ventromedial nucleus; ; dorsomedial hypothalamic nucleus; ; nucleus accumbens;
	More reference expression data
	More reference expression data
Gene ontology
Molecular function	protein binding ; polyubiquitin modification-dependent protein binding ;
Cellular component	cytoplasm ; autophagosome ; plasma membrane ; cytoplasmic vesicle ; nucleus ; membrane ; cytosol ;
Biological process	autophagy ; regulation of autophagosome assembly ; negative regulation of G protein-coupled receptor internalization ; regulation of macroautophagy ; ubiquitin-dependent ERAD pathway ; negative regulation of clathrin-dependent endocytosis ; positive regulation of ER-associated ubiquitin-dependent protein catabolic process ; autophagosome assembly ; ubiquitin-dependent protein catabolic process ;
	Sources:Amigo / QuickGO
Orthologs
	29978
	54609
	ENSG00000188021
	ENSMUSG00000050148
	Q9UHD9
	Q9QZM0
	NM_013444
	NM_018798
	NP_038472
	NP_061268
	Wikidata
View/Edit Human	View/Edit Mouse

Last updated October 08, 2023

Ubiquilin-2 is a protein that in humans is encoded by the UBQLN2 gene.^[5]^[6]

Function

This gene encodes a ubiquitin-like protein (ubiquilin) that shares high degree of similarity with related products in yeast, rat and frog. Ubiquilins contain a N-terminal ubiquitin-like domain and a C-terminal ubiquitin-associated domain. They physically associate with both proteasomes and ubiquitin ligases, and are thus thought to functionally link the ubiquitination machinery to the proteasome to effect in vivo protein degradation. This ubiquilin has also been shown to bind the ATPase domain of the Hsp70-like Hspa13 (Stch) protein.^[6]

Similarity to other proteins

Human UBQLN2 shares a high degree of similarity with related ubiquilins including UBQLN1 and UBQLN4.^[7]

Clinical significance

In a small proportion of familial amyotrophic lateral sclerosis (fALS), the UBQLN2 gene is mutated, causing formation of a non-functional Ubiquilin 2 enzyme. This non-functioning enzyme leads to the accumulation of ubiquinated proteins in the lower motor neurons and upper corticospinal motor neurons, due to the fact that ubiquilin 2 normally degrades these ubiquinated proteins, but cannot if the ALS mutation is present.^[8] The same accumulations occur in patients without UBQLN2 mutations, but with mutations in other genes, including TDP-43 and C9ORF72.^{[ citation needed ]}

Interactions

UBQLN2 has been shown to interact with HERPUD1 ^[9] and UBE3A.^[10]

Related Research Articles

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.

SUMO-conjugating enzyme UBC9 is an enzyme that in humans is encoded by the UBE2I gene. It is also sometimes referred to as "ubiquitin conjugating enzyme E2I" or "ubiquitin carrier protein 9", even though these names do not accurately describe its function.

Cullin 1, also known as CUL1, is a human protein and gene from cullin family. This protein plays an important role in protein degradation and protein ubiquitination.

26S proteasome non-ATPase regulatory subunit 10 or gankyrin is an enzyme that in humans is encoded by the PSMD10 gene. First isolated in 1998 by Tanaka et al.; Gankyrin is an oncoprotein that is a component of the 19S regulatory cap of the proteasome. Structurally, it contains a 33-amino acid ankyrin repeat that forms a series of alpha helices. It plays a key role in regulating the cell cycle via protein-protein interactions with the cyclin-dependent kinase CDK4. It also binds closely to the E3 ubiquitin ligase MDM2, which is a regulator of the degradation of p53 and retinoblastoma protein, both transcription factors involved in tumor suppression and found mutated in many cancers. Gankyrin also has an anti-apoptotic effect and is overexpressed in certain types of tumor cells such as hepatocellular carcinoma.

26S proteasome non-ATPase regulatory subunit 4, also as known as 26S Proteasome Regulatory Subunit Rpn10, is an enzyme that in humans is encoded by the PSMD4 gene. This protein is one of the 19 essential subunits that contributes to the complete assembly of 19S proteasome complex.

Proteasome subunit beta type-5 as known as 20S proteasome subunit beta-5 is a protein that in humans is encoded by the PSMB5 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex. In particular, proteasome subunit beta type-5, along with other beta subunits, assemble into two heptameric rings and subsequently a proteolytic chamber for substrate degradation. This protein contains "chymotrypsin-like" activity and is capable of cleaving after large hydrophobic residues of peptide. The eukaryotic proteasome recognized degradable proteins, including damaged proteins for protein quality control purpose or key regulatory protein components for dynamic biological processes. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides.

26S protease regulatory subunit 4, also known as 26S proteasome AAA-ATPase subunit Rpt2, is an enzyme that in humans is encoded by the PSMC1 gene. This protein is one of the 19 essential subunits of a complete assembled 19S proteasome complex. Six 26S proteasome AAA-ATPase subunits together with four non-ATPase subunits form the base sub complex of 19S regulatory particle for proteasome complex.

Proteasome subunit alpha type-2 is a protein that in humans is encoded by the PSMA2 gene. This protein is one of the 17 essential subunits that contributes to the complete assembly of 20S proteasome complex.

Ubiquilin-1 is a protein that in humans is encoded by the UBQLN1 gene.

40S ribosomal protein S27a is a protein that in humans is encoded by the RPS27A gene.

Cyclin-dependent kinases regulatory subunit 1 is a protein that in humans is encoded by the CKS1B gene.

RING-box protein 2 is a protein that in humans is encoded by the RNF7 gene.

Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.

DNA excision repair protein ERCC-8 is a protein that in humans is encoded by the ERCC8 gene.

Ubiquitin conjugation factor E4 B is a protein that in humans is encoded by the UBE4B gene.

E3 ubiquitin-protein ligase RNF19A is an enzyme that in humans is encoded by the RNF19A gene.

Ubiquitin-conjugating enzyme E2 J1 is a protein that in humans is encoded by the UBE2J1 gene.

NEDD8-conjugating enzyme Ubc12 is a protein that in humans is encoded by the UBE2M gene.

References

1 2 3 GRCh38: Ensembl release 89: ENSG00000188021 - Ensembl, May 2017
1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050148 - Ensembl, May 2017
↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
↑ Kaye FJ, Modi S, Ivanovska I, Koonin EV, Thress K, Kubo A, Kornbluth S, Rose MD (Mar 2000). "A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch". FEBS Lett. 467 (2–3): 348–55. doi: 10.1016/S0014-5793(00)01135-2 . PMID 10675567.
1 2 "Entrez Gene: UBQLN2 ubiquilin 2".
↑ Marín I (March 2014). "The ubiquilin gene family: evolutionary patterns and functional insights". BMC Evol Biol. 14: 63. doi:10.1186/1471-2148-14-63. PMC 4230246 . PMID 24674348.
↑
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 (August 2011). "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia". Nature. 477 (7363): 211–215. Bibcode:2011Natur.477..211D. doi:10.1038/nature10353. PMC 3169705 . PMID 21857683.
- Amanda Schaffer (August 29, 2011). "Possible Culprit Is Found for Lou Gehrig's Disease" . The New York Times.
↑ Kim TY, Kim E, Yoon SK, Yoon JB (May 2008). "Herp enhances ER-associated protein degradation by recruiting ubiquilins". Biochem. Biophys. Res. Commun. 369 (2): 741–6. doi:10.1016/j.bbrc.2008.02.086. PMID 18307982.
↑ Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (August 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Mol. Cell. 6 (2): 409–19. doi: 10.1016/S1097-2765(00)00040-X . PMID 10983987.

Ueki N, Oda T, Kondo M, et al. (1999). "Selection system for genes encoding nuclear-targeted proteins". Nat. Biotechnol. 16 (13): 1338–42. doi:10.1038/4315. PMID 9853615. S2CID 20001769.
Kaye FJ, Shows TB (2000). "Assignment of ubiquilin2 (UBQLN2) to human chromosome xp11. 23→p11.1 by GeneBridge radiation hybrids". Cytogenet. Cell Genet. 89 (1–2): 116–7. doi:10.1159/000015588. PMID 10894951. S2CID 43380537.
Kleijnen MF, Shih AH, Zhou P, et al. (2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Mol. Cell. 6 (2): 409–19. doi: 10.1016/S1097-2765(00)00040-X . PMID 10983987.
Murillas R, Simms KS, Hatakeyama S, et al. (2002). "Identification of developmentally expressed proteins that functionally interact with Nedd4 ubiquitin ligase". J. Biol. Chem. 277 (4): 2897–907. doi: 10.1074/jbc.M110047200 . PMID 11717310.
Walters KJ, Kleijnen MF, Goh AM, et al. (2002). "Structural studies of the interaction between ubiquitin family proteins and proteasome subunit S5a". Biochemistry. 41 (6): 1767–77. doi:10.1021/bi011892y. PMID 11827521.
Saeki Y, Sone T, Toh-e A, Yokosawa H (2002). "Identification of ubiquitin-like protein-binding subunits of the 26S proteasome". Biochem. Biophys. Res. Commun. 296 (4): 813–9. doi:10.1016/S0006-291X(02)02002-8. PMID 12200120.
Strausberg RL, Feingold EA, Grouse LH, et al. (2003). "Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences". Proc. Natl. Acad. Sci. U.S.A. 99 (26): 16899–903. Bibcode:2002PNAS...9916899M. doi: 10.1073/pnas.242603899 . PMC 139241 . PMID 12477932.
Kleijnen MF, Alarcon RM, Howley PM (2004). "The ubiquitin-associated domain of hPLIC-2 interacts with the proteasome". Mol. Biol. Cell. 14 (9): 3868–75. doi:10.1091/mbc.E02-11-0766. PMC 196580 . PMID 12972570.
Colland F, Jacq X, Trouplin V, et al. (2004). "Functional proteomics mapping of a human signaling pathway". Genome Res. 14 (7): 1324–32. doi:10.1101/gr.2334104. PMC 442148 . PMID 15231748.
Ross MT, Grafham DV, Coffey AJ, et al. (2005). "The DNA sequence of the human X chromosome". Nature. 434 (7031): 325–37. Bibcode:2005Natur.434..325R. doi:10.1038/nature03440. PMC 2665286 . PMID 15772651.
Massey LK, Mah AL, Monteiro MJ (2006). "Ubiquilin regulates presenilin endoproteolysis and modulates gamma-secretase components, Pen-2 and nicastrin". Biochem. J. 391 (Pt 3): 513–25. doi:10.1042/BJ20050491. PMC 1276952 . PMID 15975090.
Lim J, Hao T, Shaw C, et al. (2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi: 10.1016/j.cell.2006.03.032 . PMID 16713569.
Ford DL, Monteiro MJ (2006). "Dimerization of ubiquilin is dependent upon the central region of the protein: evidence that the monomer, but not the dimer, is involved in binding presenilins". Biochem. J. 399 (3): 397–404. doi:10.1042/BJ20060441. PMC 1615901 . PMID 16813565.
Kang Y, Zhang N, Koepp DM, Walters KJ (2007). "Ubiquitin receptor proteins hHR23a and hPLIC2 interact". J. Mol. Biol. 365 (4): 1093–101. doi:10.1016/j.jmb.2006.10.056. PMC 1994665 . PMID 17098253.

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[refGRCh38Ensembl-1] 1 2 3 GRCh38: Ensembl release 89: ENSG00000188021 - Ensembl, May 2017

[refGRCm38Ensembl-2] 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000050148 - Ensembl, May 2017

[3] "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[4] "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.

[pmid10675567-5] Kaye FJ, Modi S, Ivanovska I, Koonin EV, Thress K, Kubo A, Kornbluth S, Rose MD (Mar 2000). "A family of ubiquitin-like proteins binds the ATPase domain of Hsp70-like Stch". FEBS Lett. 467 (2–3): 348–55. doi: 10.1016/S0014-5793(00)01135-2 . PMID 10675567.

[entrez-6] 1 2 "Entrez Gene: UBQLN2 ubiquilin 2".

[pmid24674348-7] Marín I (March 2014). "The ubiquilin gene family: evolutionary patterns and functional insights". BMC Evol Biol. 14: 63. doi:10.1186/1471-2148-14-63. PMC 4230246 . PMID 24674348.

[pmid21857683-8] 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 (August 2011). "Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ALS and ALS/dementia". Nature. 477 (7363): 211–215. Bibcode:2011Natur.477..211D. doi:10.1038/nature10353. PMC 3169705 . PMID 21857683.
Amanda Schaffer (August 29, 2011). "Possible Culprit Is Found for Lou Gehrig's Disease" . The New York Times.

[mwog] Amanda Schaffer (August 29, 2011). "Possible Culprit Is Found for Lou Gehrig's Disease" . The New York Times.

[pmid18307982-9] Kim TY, Kim E, Yoon SK, Yoon JB (May 2008). "Herp enhances ER-associated protein degradation by recruiting ubiquilins". Biochem. Biophys. Res. Commun. 369 (2): 741–6. doi:10.1016/j.bbrc.2008.02.086. PMID 18307982.

[pmid10983987-10] Kleijnen MF, Shih AH, Zhou P, Kumar S, Soccio RE, Kedersha NL, Gill G, Howley PM (August 2000). "The hPLIC proteins may provide a link between the ubiquitination machinery and the proteasome". Mol. Cell. 6 (2): 409–19. doi: 10.1016/S1097-2765(00)00040-X . PMID 10983987.

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