Ubiquitin-protein ligase E3B

Ubiquitin-Protein Ligase E3B (UBE3B) is an enzyme encoded by UBE3B gene in humans. UBE3B has an N-terminal IQ motif, which mediates calcium-independent calmodulin binding[5] and a large C-terminal catalytic HECT domain.

UBE3B
Identifiers
AliasesUBE3B, BPIDS, KOS, ubiquitin protein ligase E3B
External IDsOMIM: 608047; MGI: 1891295; HomoloGene: 13775; GeneCards: UBE3B; OMA:UBE3B - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_054093
NM_001331219

RefSeq (protein)

NP_001257378
NP_001257379
NP_001257380
NP_569733
NP_904324

NP_001318148
NP_473434

Location (UCSC)Chr 12: 109.48 – 109.54 MbChr 5: 114.52 – 114.56 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Discovery

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UBE3B gene was discovered in 1996 by the group of Margaret Lomax at the University of Michigan Medical School.[6] Differential mRNA expression study, to reveal genes upregulated after acoustic trauma in the chick basilar papilla, led to identification of cDNA which exhibited 84% of identity of uncharacterized human cDNA.[7] Interestingly, its expression dramatically increased in the regions of damaged chick inner ear upon noise-induced trauma. In 2003, human and mouse UBE3B gene was cloned and characterized by its discoverers.[6]

Clinical significance

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Inactivating mutations in UBE3B gene have been linked to Kaufman oculocerebrofacial syndrome (KOS),[8][9][10][11][12][13][14] a severe developmental disorder. Most mutations are loss-of-function and lead to premature stop codon. However, some mutations are of single amino acid substitution type and these occur in the low complexity region, or in the catalytic HECT domain.

Mouse models

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Deletion of murine ortholog Ube3b leads to severe developmental delay in mice.[15][16] The conventional knockout of Ube3b leads to a growth retardation, decreased grip strength, and loss of vocalization associated with the metabolic disease with nucleotide metabolism and the tricarboxylic acid cycle being the most affected. Such metabolic disturbances were also found in KOS patients. In this context, UBE3B ubiquitinated α-ketoacid dehydrogenase kinase (BCKDK).[15] Forebrain-specific conditional Ube3b knockout mice showed impaired spatial learning, altered social interactions, and repetitive behaviors. Ube3b knockout neurons exhibited decreased dendritic branching, increased density and aberrant morphology of dendritic spines, altered synaptic physiology, and changes in hippocampal circuit activity. Dendritic and spine phenotype was regulated by Ube3b in a cell-autonomous manner. Murine Ube3b ubiquitinated the catalytic γ-subunit of calcineurin, Ppp3cc, the overexpression of which phenocopied Ube3b loss with regard to dendrite branching and dendritic spine density.[16]

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000151148Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029577Ensembl, 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.
  5. ^ Braganza A, Li J, Zeng X, Yates NA, Dey NB, Andrews J, et al. (February 2017). "UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase". The Journal of Biological Chemistry. 292 (6): 2470–2484. doi:10.1074/jbc.M116.766824. PMC 5313114. PMID 28003368.
  6. ^ a b Gong TW, Huang L, Warner SJ, Lomax MI (August 2003). "Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing". Genomics. 82 (2): 143–152. doi:10.1016/s0888-7543(03)00111-3. PMID 12837265.
  7. ^ Lomax MI, Gong TW, Cho Y, Huang L, Oh SH, Adler HJ, et al. (2001). "Differential Gene Expression Following Noise Trauma in Birds and Mammals". Noise & Health. 3 (11): 19–35. PMID 12689446.
  8. ^ Galarreta CI, Wigby KM, Jones MC (October 2019). "Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review". Clinical Dysmorphology. 28 (4): 175–183. doi:10.1097/MCD.0000000000000282. PMID 31162149. S2CID 174808266.
  9. ^ Yilmaz R, Szakszon K, Altmann A, Altunoglu U, Senturk L, McGuire M, et al. (January 2018). "Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients". American Journal of Medical Genetics. Part A. 176 (1): 187–193. doi:10.1002/ajmg.a.38538. PMID 29160006. S2CID 24437121.
  10. ^ Brabbing-Goldstein D, Basel-Salmon L (1993). "Kaufman Oculocerebrofacial Syndrome". In Adam MP, Ardinger HH, Pagon RA, Wallace SE (eds.). GeneReviews®. University of Washington, Seattle. PMID 27763745. Retrieved 2020-05-05.
  11. ^ Pedurupillay CR, Barøy T, Holmgren A, Blomhoff A, Vigeland MD, Sheng Y, et al. (March 2015). "Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B". American Journal of Medical Genetics. Part A. 167A (3): 657–663. doi:10.1002/ajmg.a.36944. PMID 25691420. S2CID 205320002.
  12. ^ Basel-Vanagaite L, Yilmaz R, Tang S, Reuter MS, Rahner N, Grange DK, et al. (July 2014). "Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations" (PDF). Human Genetics. 133 (7): 939–949. doi:10.1007/s00439-014-1436-2. PMID 24615390. S2CID 17410752.
  13. ^ Flex E, Ciolfi A, Caputo V, Fodale V, Leoni C, Melis D, et al. (August 2013). "Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome". Journal of Medical Genetics. 50 (8): 493–499. doi:10.1136/jmedgenet-2012-101405. PMC 3717725. PMID 23687348.
  14. ^ Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, et al. (December 2012). "Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome". American Journal of Human Genetics. 91 (6): 998–1010. doi:10.1016/j.ajhg.2012.10.011. PMC 3516591. PMID 23200864.
  15. ^ a b Cheon S, Kaur K, Nijem N, Tuncay IO, Kumar P, Dean M, et al. (February 2019). "The ubiquitin ligase UBE3B, disrupted in intellectual disability and absent speech, regulates metabolic pathways by targeting BCKDK". Proceedings of the National Academy of Sciences of the United States of America. 116 (9): 3662–3667. Bibcode:2019PNAS..116.3662C. doi:10.1073/pnas.1818751116. PMC 6397573. PMID 30808755.
  16. ^ a b Ambrozkiewicz MC, Borisova E, Schwark M, Ripamonti S, Schaub T, Smorodchenko A, et al. (June 2021). "The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc". Molecular Psychiatry. 26 (6): 1980–1995. doi:10.1038/s41380-020-0714-8. PMID 32249816. S2CID 214798478.