Tubulin beta-4A chain explained

Tubulin beta-4A chain is a protein that in humans is encoded by the TUBB4A gene. Two tubulin beta-4 chain proteins are encoded in the human genome by the genes TUBB4A (this entry) and TUBB4B.^{[1] [2] [3]} Tubulin is the major constituent of microtubules, a key components of the cytoskeleton. It binds two molecules of GTP, one at an exchangeable site on the beta-chain and one at a non-exchangeable site on the alpha-chain. TUBB4A is preferentially and highly expressed in the central nervous system.^[4]

Clinical significance

Mutations in TUBB4A have been associated with two neurological disorders.

An R2G substitution in the autoregulatory MREI domain of TUBB4A has been identified as the cause of 'hereditary whispering dysphonia' or DYT4.^[5]

A de novo D249N mutation has been identified as the cause of a rare leukoencephalopathy, hypomyelination with atrophy of basal ganglia and cerebellum (H-ABC).^[6]

Mutations in TUBB4A are associated with Pelizaeus–Merzbacher disease.^[7]

Further reading

• Wang D, Villasante A, Lewis SA, Cowan NJ . The mammalian beta-tubulin repertoire: hematopoietic expression of a novel, heterologous beta-tubulin isotype. . Journal of Cell Biology . 103 . 5 . 1903–1910 . 1987 . 3782288 . 10.1083/jcb.103.5.1903 . 2114403 .
• Baumann MH, Wisniewski T, Levy E, etal . C-terminal fragments of alpha- and beta-tubulin form amyloid fibrils in vitro and associate with amyloid deposits of familial cerebral amyloid angiopathy, British type. . Biochem. Biophys. Res. Commun. . 219 . 1 . 238–242 . 1996 . 8619814 . 10.1006/bbrc.1996.0211 . free .
• Watts NR, Sackett DL, Ward RD, etal . HIV-1 rev depolymerizes microtubules to form stable bilayered rings. . Journal of Cell Biology . 150 . 2 . 349–360 . 2000 . 10908577 . 10.1083/jcb.150.2.349 . 2180222 .
• Tarazona R, López-Lluch G, Galiani MD, etal . HLA-B2702 (77-83/83-77) peptide binds to beta-tubulin on human NK cells and blocks their cytotoxic capacity. . Journal of Immunology . 165 . 12 . 6776–6782 . 2001 . 11120798 . 10.4049/jimmunol.165.12.6776. free .
• Strausberg RL, Feingold EA, Grouse LH, etal . Generation and initial analysis of more than 15,000 full-length human and mouse cDNA sequences. . Proceedings of the National Academy of Sciences of the United States of America . 99 . 26 . 16899–16903 . 2003 . 12477932 . 10.1073/pnas.242603899 . 139241 . 2002PNAS...9916899M . free .
• Chen D, Wang M, Zhou S, Zhou Q . HIV-1 Tat targets microtubules to induce apoptosis, a process promoted by the pro-apoptotic Bcl-2 relative Bim. . EMBO Journal . 21 . 24 . 6801–6810 . 2004 . 12486001 . 10.1093/emboj/cdf683 . 139103 .
• Zhang C, Dowd DR, Staal A, etal . Nuclear coactivator-62 kDa/Ski-interacting protein is a nuclear matrix-associated coactivator that may couple vitamin D receptor-mediated transcription and RNA splicing. . Journal of Biological Chemistry . 278 . 37 . 35325–35336 . 2003 . 12840015 . 10.1074/jbc.M305191200 . free .
• Ota T, Suzuki Y, Nishikawa T, etal . Complete sequencing and characterization of 21,243 full-length human cDNAs. . Nature Genetics . 36 . 1 . 40–45 . 2004 . 14702039 . 10.1038/ng1285 . free .
• Bouwmeester T, Bauch A, Ruffner H, etal . A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. . Nature Cell Biology . 6 . 2 . 97–105 . 2004 . 14743216 . 10.1038/ncb1086 . 11683986 .
• Villacé P, Marión RM, Ortín J . The composition of Staufen-containing RNA granules from human cells indicates their role in the regulated transport and translation of messenger RNAs. . Nucleic Acids Research . 32 . 8 . 2411–2420 . 2004 . 15121898 . 10.1093/nar/gkh552 . 419443 .
• Hassel S, Eichner A, Yakymovych M, etal . Proteins associated with type II bone morphogenetic protein receptor (BMPR-II) and identified by two-dimensional gel electrophoresis and mass spectrometry. . Proteomics . 4 . 5 . 1346–1358 . 2004 . 15188402 . 10.1002/pmic.200300770 . 6773754 .
• Jin J, Smith FD, Stark C, etal . Proteomic, functional, and domain-based analysis of in vivo 14-3-3 binding proteins involved in cytoskeletal regulation and cellular organization. . Curr. Biol. . 14 . 16 . 1436–1450 . 2004 . 15324660 . 10.1016/j.cub.2004.07.051 . free .
• Campbell GR, Pasquier E, Watkins J, etal . The glutamine-rich region of the HIV-1 Tat protein is involved in T-cell apoptosis. . Journal of Biological Chemistry . 279 . 46 . 48197–48204 . 2005 . 15331610 . 10.1074/jbc.M406195200 . free .
• Gerhard DS, Wagner L, Feingold EA, etal . The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). . Genome Research . 14 . 10B . 2121–7 . 2004 . 15489334 . 10.1101/gr.2596504 . 528928 .
• de Mareuil J, Carre M, Barbier P, etal . HIV-1 Tat protein enhances microtubule polymerization. . Retrovirology . 2 . 5 . 2006 . 15691386 . 10.1186/1742-4690-2-5 . 549075 . free .
• Giacca M . HIV-1 Tat, apoptosis and the mitochondria: a tubulin link? . Retrovirology . 2 . 7 . 2006 . 15698476 . 10.1186/1742-4690-2-7 . 549042 . free .
• Otsuki T, Ota T, Nishikawa T, etal . Signal sequence and keyword trap in silico for selection of full-length human cDNAs encoding secretion or membrane proteins from oligo-capped cDNA libraries. . DNA Res. . 12 . 2 . 117–126 . 2007 . 16303743 . 10.1093/dnares/12.2.117 . free .
• Coiras M, Camafeita E, Ureña T, etal . Modifications in the human T cell proteome induced by intracellular HIV-1 Tat protein expression. . Proteomics . 6 . S63–7S3 . 2006. Suppl 1 . 16526095 . 10.1002/pmic.200500437 . 42878271 .

Notes and References

1. Hall JL, Dudley L, Dobner PR, Lewis SA, Cowan NJ . Identification of two human beta-tubulin isotypes . Molecular and Cellular Biology . 3 . 5 . 854–862 . Aug 1983 . 6865944 . 368608 . 10.1128/mcb.3.5.854.
2. Lee MG, Loomis C, Cowan NJ . Sequence of an expressed human beta-tubulin gene containing ten Alu family members . Nucleic Acids Research . 12 . 14 . 5823–5836 . Sep 1984 . 6462917 . 320034 . 10.1093/nar/12.14.5823 .
3. Web site: Entrez Gene: TUBB4 tubulin, beta 4.
4. Web site: UCSC Genome Browser: TUBB4A microarray expression .
5. Hersheson J, Mencacci NE, Davis M, Macdonald N, Trabzuni D, Ryten M, Pittman A, Paudel R, Kara E, Fawcett K, Plagnol V, Bhatia KP, Medlar AJ, Stanescu HC, Hardy J, Kleta R, Wood NW, Houlden H . Mutations in the autoregulatory domain of β-tubulin 4a cause hereditary dystonia . Annals of Neurology . 73. 4. 546–553. December 2012 . 23424103 . 10.1002/ana.23832 . 3698699.
6. Simons C, Wolf NI, McNeil N, Caldovic L, Devaney JM, Takanohashi A, Crawford J, Ru K, Grimmond SM, Miller D, Tonduti D, Schmidt JL, Chudnow RS, van Coster R, Lagae L, Kisler J, Sperner J, van der Knaap MS, Schiffmann R, Taft RJ, Vanderver A . A de novo mutation in the β-tubulin gene TUBB4A results in the leukoencephalopathy hypomyelination with atrophy of the basal ganglia and cerebellum . American Journal of Human Genetics . 92 . 5 . 767–773 . May 2013 . 23582646 . 10.1016/j.ajhg.2013.03.018 . 3644625.
7. 24974158. 2014. Shimojima. K. A de novo TUBB4A mutation in a patient with hypomyelination mimicking Pelizaeus-Merzbacher disease. Brain & Development. Okumura. A. Ikeno. M. Nishimura. A. Saito. A. Saitsu. H. Matsumoto. N. Yamamoto. T. 10.1016/j.braindev.2014.05.004 . 37 . 3. 281–285. free.