Biology:Ubiquitin-Protein Ligase E3B

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Short description: Protein-coding gene in Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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[1] and a large C-terminal catalytic HECT domain.

Gene discovery

UBE3B gene was discovered in 1996 by the group of Margaret Lomax at the University of Michigan Medical School.[2] 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.[3] 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.[2]

Clinical significance

Inactivating mutations in UBE3B gene have been linked to Kaufman oculocerebrofacial syndrome (KOS),[4][5][6][7][8][9][10] 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 of Ube3b deficiency and UBE3B/Ube3b targets

Deletion of murine ortholog Ube3b leads to severe developmental delay in mice.[11][12] 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).[11] 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.[12]

References

  1. ↑ Braganza, Andrea; Li, Jianfeng; Zeng, Xuemei; Yates, Nathan A.; Dey, Nupur B.; Andrews, Joel; Clark, Jennifer; Zamani, Leila et al. (2017-10-02). "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. ISSN 1083-351X. PMID 28003368. 
  2. ↑ 2.0 2.1 Gong, Tzy-Wen L.; Huang, Li; Warner, Steven J.; Lomax, Margaret I. (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. ISSN 0888-7543. PMID 12837265. 
  3. ↑ Lomax, Margaret I.; Gong, Tzy-Wen; Cho, Younsook; Huang, Li; Oh, Seung-Ha; Adler, Henry J.; Raphael, Yehoash; Altschuler, Richard A. (2001). "Differential Gene Expression Following Noise Trauma in Birds and Mammals". Noise & Health 3 (11): 19–35. ISSN 1463-1741. PMID 12689446. 
  4. ↑ Galarreta, Carolina I.; Wigby, Kristen M.; Jones, Marilyn C. (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. ISSN 1473-5717. PMID 31162149. 
  5. ↑ Yilmaz, Rüstem; Szakszon, Katalin; Altmann, Anna; Altunoglu, Umut; Senturk, Leyli; McGuire, Marianne; Calabrese, Olga; Madan-Khetarpal, Suneeta 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. ISSN 1552-4833. PMID 29160006. 
  6. ↑ Basel-Vanagaite, Lina; Borck, Guntram (1993), Adam, Margaret P.; Ardinger, Holly H.; Pagon, Roberta A. et al., eds., "Kaufman Oculocerebrofacial Syndrome", GeneReviews® (University of Washington, Seattle), PMID 27763745, http://www.ncbi.nlm.nih.gov/books/NBK390670/, retrieved 2020-05-05 
  7. ↑ Pedurupillay, Christeen Ramane J.; Barøy, Tuva; Holmgren, Asbjørn; Blomhoff, Anne; Vigeland, Magnus D.; Sheng, Ying; Frengen, Eirik; Strømme, Petter 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. ISSN 1552-4833. PMID 25691420. 
  8. ↑ Basel-Vanagaite, Lina; Yilmaz, Rüstem; Tang, Sha; Reuter, Miriam S.; Rahner, Nils; Grange, Dorothy K.; Mortenson, Megan; Koty, Patrick et al. (July 2014). "Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations". Human Genetics 133 (7): 939–949. doi:10.1007/s00439-014-1436-2. ISSN 1432-1203. PMID 24615390. http://doc.rero.ch/record/325553/files/439_2014_Article_1436.pdf. 
  9. ↑ Flex, Elisabetta; Ciolfi, Andrea; Caputo, Viviana; Fodale, Valentina; Leoni, Chiara; Melis, Daniela; Bedeschi, Maria Francesca; Mazzanti, Laura et al. (August 2018). "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. ISSN 1468-6244. PMID 23687348. 
  10. ↑ Basel-Vanagaite, Lina; Dallapiccola, Bruno; Ramirez-Solis, Ramiro; Segref, Alexandra; Thiele, Holger; Edwards, Andrew; Arends, Mark J.; Miró, Xavier et al. (2012-12-07). "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. ISSN 1537-6605. PMID 23200864. 
  11. ↑ 11.0 11.1 Cheon, Solmi; Kaur, Kiran; Nijem, Nadine; Tuncay, Islam Oguz; Kumar, Pooja; Dean, Milan; Juusola, Jane; Guillen-Sacoto, Maria J. et al. (2019-02-26). "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. doi:10.1073/pnas.1818751116. ISSN 1091-6490. PMID 30808755. Bibcode: 2019PNAS..116.3662C. 
  12. ↑ 12.0 12.1 Ambrozkiewicz, Mateusz C.; Borisova, Ekaterina; Schwark, Manuela; Ripamonti, Silvia; Schaub, Theres; Smorodchenko, Alina; Weber, A. Ioana; Rhee, Hong Jun et al. (2020-04-06). "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. ISSN 1476-5578. PMID 32249816. 




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