Ubiquitin-protein ligase E3B explained

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.

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.

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

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). 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.

Notes and References

  1. Braganza A, Li J, Zeng X, Yates NA, Dey NB, Andrews J, Clark J, Zamani L, Wang XH, St Croix C, O'Sullivan R, Garcia-Exposito L, Brodsky JL, Sobol RW . 6 . UBE3B Is a Calmodulin-regulated, Mitochondrion-associated E3 Ubiquitin Ligase . The Journal of Biological Chemistry . 292 . 6 . 2470–2484 . February 2017 . 28003368 . 5313114 . 10.1074/jbc.M116.766824 . free .
  2. Gong TW, Huang L, Warner SJ, Lomax MI . Characterization of the human UBE3B gene: structure, expression, evolution, and alternative splicing . Genomics . 82 . 2 . 143–152 . August 2003 . 12837265 . 10.1016/s0888-7543(03)00111-3 .
  3. Lomax MI, Gong TW, Cho Y, Huang L, Oh SH, Adler HJ, Raphael Y, Altschuler RA . 6 . Differential Gene Expression Following Noise Trauma in Birds and Mammals . Noise & Health . 3 . 11 . 19–35 . 2001 . 12689446 .
  4. Galarreta CI, Wigby KM, Jones MC . Further phenotypic characterization of Kaufman oculocerebrofacial syndrome: report of five new cases and literature review . Clinical Dysmorphology . 28 . 4 . 175–183 . October 2019 . 31162149 . 10.1097/MCD.0000000000000282 . 174808266 .
  5. Yilmaz R, Szakszon K, Altmann A, Altunoglu U, Senturk L, McGuire M, Calabrese O, Madan-Khetarpal S, Basel-Vanagaite L, Borck G . 6 . Kaufman oculocerebrofacial syndrome: Novel UBE3B mutations and clinical features in four unrelated patients . American Journal of Medical Genetics. Part A . 176 . 1 . 187–193 . January 2018 . 29160006 . 10.1002/ajmg.a.38538 . 24437121 .
  6. Book: Brabbing-Goldstein D, Basel-Salmon L . Kaufman Oculocerebrofacial Syndrome. 1993. http://www.ncbi.nlm.nih.gov/books/NBK390670/. GeneReviews®. Adam MP, Ardinger HH, Pagon RA, Wallace SE . University of Washington, Seattle. 27763745. 2020-05-05 .
  7. Pedurupillay CR, Barøy T, Holmgren A, Blomhoff A, Vigeland MD, Sheng Y, Frengen E, Strømme P, Misceo D . 6 . Kaufman oculocerebrofacial syndrome in sisters with novel compound heterozygous mutation in UBE3B . American Journal of Medical Genetics. Part A . 167A . 3 . 657–663 . March 2015 . 25691420 . 10.1002/ajmg.a.36944 . 205320002 .
  8. Basel-Vanagaite L, Yilmaz R, Tang S, Reuter MS, Rahner N, Grange DK, Mortenson M, Koty P, Feenstra H, Farwell Gonzalez KD, Sticht H, Boddaert N, Désir J, Anyane-Yeboa K, Zweier C, Reis A, Kubisch C, Jewett T, Zeng W, Borck G . 6 . Expanding the clinical and mutational spectrum of Kaufman oculocerebrofacial syndrome with biallelic UBE3B mutations . Human Genetics . 133 . 7 . 939–949 . July 2014 . 24615390 . 10.1007/s00439-014-1436-2 . 17410752 .
  9. Flex E, Ciolfi A, Caputo V, Fodale V, Leoni C, Melis D, Bedeschi MF, Mazzanti L, Pizzuti A, Tartaglia M, Zampino G . 6 . Loss of function of the E3 ubiquitin-protein ligase UBE3B causes Kaufman oculocerebrofacial syndrome . Journal of Medical Genetics . 50 . 8 . 493–499 . August 2013 . 23687348 . 3717725 . 10.1136/jmedgenet-2012-101405 .
  10. Basel-Vanagaite L, Dallapiccola B, Ramirez-Solis R, Segref A, Thiele H, Edwards A, Arends MJ, Miró X, White JK, Désir J, Abramowicz M, Dentici ML, Lepri F, Hofmann K, Har-Zahav A, Ryder E, Karp NA, Estabel J, Gerdin AK, Podrini C, Ingham NJ, Altmüller J, Nürnberg G, Frommolt P, Abdelhak S, Pasmanik-Chor M, Konen O, Kelley RI, Shohat M, Nürnberg P, Flint J, Steel KP, Hoppe T, Kubisch C, Adams DJ, Borck G . 6 . Deficiency for the ubiquitin ligase UBE3B in a blepharophimosis-ptosis-intellectual-disability syndrome . American Journal of Human Genetics . 91 . 6 . 998–1010 . December 2012 . 23200864 . 3516591 . 10.1016/j.ajhg.2012.10.011 .
  11. Cheon S, Kaur K, Nijem N, Tuncay IO, Kumar P, Dean M, Juusola J, Guillen-Sacoto MJ, Bedoukian E, Ierardi-Curto L, Kaplan P, Schaefer GB, Mishra P, Chahrour MH . 6 . 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 . February 2019 . 30808755 . 6397573 . 10.1073/pnas.1818751116 . free . 2019PNAS..116.3662C .
  12. Ambrozkiewicz MC, Borisova E, Schwark M, Ripamonti S, Schaub T, Smorodchenko A, Weber AI, Rhee HJ, Altas B, Yilmaz R, Mueller S, Piepkorn L, Horan ST, Straussberg R, Zaqout S, Jahn O, Dere E, Rosário M, Boehm-Sturm P, Borck G, Willig KI, Rhee J, Tarabykin V, Kawabe H . 6 . The murine ortholog of Kaufman oculocerebrofacial syndrome protein Ube3b regulates synapse number by ubiquitinating Ppp3cc . Molecular Psychiatry . 26 . 6 . 1980–1995 . June 2021 . 32249816 . 10.1038/s41380-020-0714-8 . 214798478 .

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