Tubulin alpha-1A chain explained

Tubulin alpha-1A chain is a protein that in humans is encoded by the TUBA1A gene.^{[1] [2] [3]}

Tubulin alpha-1A chain is a type of alpha-tubulin involved in the formation of microtubules, which are structural proteins that play a role in the cytoskeletal structure. Microtubules are composed of heterodimers of alpha- and beta-tubulin molecules. Tubulin alpha-1A (TUBA1A) is a primary alpha-tubulin expressed in the human fetal brain, specifically found in that structure.^[4]

Function

Microtubules of the eukaryotic cytoskeleton perform essential and diverse functions and are composed of a heterodimer of alpha and beta tubulins. The genes encoding these microtubule constituents belong to the tubulin superfamily, which is composed of six distinct families. Genes from the alpha, beta and gamma tubulin families are found in all eukaryotes. The alpha and beta tubulins represent the major components of microtubules, while gamma tubulin plays a critical role in the nucleation of microtubule assembly. There are multiple alpha and beta tubulin genes, which are highly conserved among species. This gene encodes alpha tubulin and is highly similar to mouse and rat Tuba1 gene. Northern blotting studies have shown that the gene expression is predominantly found in morphologically differentiated neurologic cells. This gene is one of three alpha-tubulin genes in a cluster on chromosome 12q.

Alpha-tubulins, including TUBA1A, are involved in neuronal development and maturation. Studies have shown that the rat homologs of human TUBA1A, such as Tα1, exhibit elevated expression during the extension of neuronal processes. In experiments where pheochromocytoma cells were cultured with Nerve Growth Factor (NGF), differentiation and the development of neuronal processes were observed, accompanied by a significant increase in Tα1 mRNA expression, while T26 mRNA expression showed minimal change.^[5]

TUBA1A is believed to play a role in neuronal migration by regulating microtubule dynamics, enabling the rapid formation and disassembly of polymers, which allows for the extension and retraction of processes necessary for nucleokinesis.^[6]

RNA in situ hybridization studies demonstrated the expression of TUBA1A in mouse embryos. Embryonic day 16.5 sections showed strong labeling in the telencephalon, diencephalon, mesencephalon, developing cerebellum, brainstem, spinal cord, and dorsal root ganglia.^[7]

Interactions

TUBA1A has been shown to interact with PAFAH1B1.^[8]

Animal models

Keays et al. describe a mouse with a mutation of the TUBA1A gene induced by N-ethyl-N-nitrosourea. The relevant point mutation resulted in S140G;^[9] the site of the mutation participates in the N-site of the formed α-tubulin, and participates in stabilizing the α-β tubulin polymer by binding GTP at this site.^[10] The S140G mutation resulted in the formation of a “compromised GTP binding pocket”. Authors note defects associated with cortical layers II/III and IV, especially in cortical neuronal migration (with respect to wild-type counterparts), showing that the S140G mutation has value as a model for detailing disease associated with the Human TUBA homolog.

Clinical significance

Mutations to the TUBA1A gene manifest clinically as Type 3 Lissencephaly. In general, lissencephaly is characterized by agyria (lacking of gyri and sulci to the brain – a smooth brain), seizure activity, failure to thrive, as well as intellectual disability and psychomotor retardation, often to a profound degree.^[7] The symptoms of Lis3 Lissencephaly are not especially different from generalized lissencephaly (Lis1, related to PAFAH1B1). Diagnosis of lissencephaly generally is made from the symptom profile, while attribution to a specific type is obtained by microarray. Treatment is symptomatic; anti-convulsive drugs for seizure activity, g-button gastrostomy to feed the child, physical therapy for muscle disorders. TUBA1A mutation is common in microlissencephaly

Further reading

• Desai A, Mitchison TJ . Tubulin and FtsZ structures: functional and therapeutic implications . BioEssays . 20 . 7 . 523–527 . July 1998 . 9722999 . 10.1002/(SICI)1521-1878(199807)20:7<523::AID-BIES1>3.0.CO;2-L .
• Oakley BR . An abundance of tubulins . Trends in Cell Biology . 10 . 12 . 537–542 . December 2000 . 11121746 . 10.1016/S0962-8924(00)01857-2 .
• Dutcher SK . The tubulin fraternity: alpha to eta . Current Opinion in Cell Biology . 13 . 1 . 49–54 . February 2001 . 11163133 . 10.1016/S0955-0674(00)00173-3 .
• Miller FD, Naus CC, Durand M, Bloom FE, Milner RJ . Isotypes of alpha-tubulin are differentially regulated during neuronal maturation . The Journal of Cell Biology . 105 . 6 Pt 2 . 3065–3073 . December 1987 . 3693406 . 2114727 . 10.1083/jcb.105.6.3065 .
• Cowan NJ, Dobner PR, Fuchs EV, Cleveland DW . Expression of human alpha-tubulin genes: interspecies conservation of 3' untranslated regions . Molecular and Cellular Biology . 3 . 10 . 1738–1745 . October 1983 . 6646120 . 370035 . 10.1128/mcb.3.10.1738 .
• Alexandrova N, Niklinski J, Bliskovsky V, Otterson GA, Blake M, Kaye FJ, Zajac-Kaye M . The N-terminal domain of c-Myc associates with alpha-tubulin and microtubules in vivo and in vitro . Molecular and Cellular Biology . 15 . 9 . 5188–5195 . September 1995 . 7651436 . 230766 . 10.1128/MCB.15.9.5188 .
• Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit . The EMBO Journal . 16 . 23 . 6977–6984 . December 1997 . 9384577 . 1170301 . 10.1093/emboj/16.23.6977 .
• Kinnunen T, Kaksonen M, Saarinen J, Kalkkinen N, Peng HB, Rauvala H . Cortactin-Src kinase signaling pathway is involved in N-syndecan-dependent neurite outgrowth . The Journal of Biological Chemistry . 273 . 17 . 10702–10708 . April 1998 . 9553134 . 10.1074/jbc.273.17.10702 . free .
• Faruki S, Geahlen RL, Asai DJ . Syk-dependent phosphorylation of microtubules in activated B-lymphocytes . Journal of Cell Science . 113 . 14 . 2557–2565 . July 2000 . 10862713 . 10.1242/jcs.113.14.2557 .
• Watts NR, Sackett DL, Ward RD, Miller MW, Wingfield PT, Stahl SS, Steven AC . HIV-1 rev depolymerizes microtubules to form stable bilayered rings . The Journal of Cell Biology . 150 . 2 . 349–360 . July 2000 . 10908577 . 2180222 . 10.1083/jcb.150.2.349 .
• Germani A, Bruzzoni-Giovanelli H, Fellous A, Gisselbrecht S, Varin-Blank N, Calvo F . SIAH-1 interacts with alpha-tubulin and degrades the kinesin Kid by the proteasome pathway during mitosis . Oncogene . 19 . 52 . 5997–6006 . December 2000 . 11146551 . 10.1038/sj.onc.1204002 . 41279377 .
• Payton JE, Perrin RJ, Clayton DF, George JM . Protein-protein interactions of alpha-synuclein in brain homogenates and transfected cells . Brain Research. Molecular Brain Research . 95 . 1–2 . 138–145 . November 2001 . 11687285 . 10.1016/S0169-328X(01)00257-1 .
• Bifulco M, Laezza C, Stingo S, Wolff J . 2',3'-Cyclic nucleotide 3'-phosphodiesterase: a membrane-bound, microtubule-associated protein and membrane anchor for tubulin . Proceedings of the National Academy of Sciences of the United States of America . 99 . 4 . 1807–1812 . February 2002 . 11842207 . 122275 . 10.1073/pnas.042678799 . free . 2002PNAS...99.1807B .
• Saugstad JA, Yang S, Pohl J, Hall RA, Conn PJ . Interaction between metabotropic glutamate receptor 7 and alpha tubulin . Journal of Neurochemistry . 80 . 6 . 980–988 . March 2002 . 11953448 . 2925652 . 10.1046/j.0022-3042.2002.00778.x .
• Ivings L, Pennington SR, Jenkins R, Weiss JL, Burgoyne RD . Identification of Ca2+-dependent binding partners for the neuronal calcium sensor protein neurocalcin delta: interaction with actin, clathrin and tubulin . The Biochemical Journal . 363 . Pt 3 . 599–608 . May 2002 . 11964161 . 1222513 . 10.1042/0264-6021:3630599 .

Notes and References

1. Crabtree DV, Ojima I, Geng X, Adler AJ . Tubulins in the primate retina: evidence that xanthophylls may be endogenous ligands for the paclitaxel-binding site . Bioorganic & Medicinal Chemistry . 9 . 8 . 1967–1976 . August 2001 . 11504633 . 10.1016/S0968-0896(01)00103-1 .
2. Hall JL, Cowan NJ . Structural features and restricted expression of a human alpha-tubulin gene . Nucleic Acids Research . 13 . 1 . 207–223 . January 1985 . 3839072 . 340985 . 10.1093/nar/13.1.207 .
3. Web site: Entrez Gene: TUBA1A tubulin, alpha 1a.
4. Cowan NJ, Dobner PR, Fuchs EV, Cleveland DW . Expression of human alpha-tubulin genes: interspecies conservation of 3' untranslated regions . Molecular and Cellular Biology . 3 . 10 . 1738–1745 . October 1983 . 6646120 . 370035 . 10.1128/mcb.3.10.1738 .
5. Miller FD, Naus CC, Durand M, Bloom FE, Milner RJ . Isotypes of alpha-tubulin are differentially regulated during neuronal maturation . The Journal of Cell Biology . 105 . 6 Pt 2 . 3065–3073 . December 1987 . 3693406 . 2114727 . 10.1083/jcb.105.6.3065 .
6. Sakakibara A, Ando R, Sapir T, Tanaka T . Microtubule dynamics in neuronal morphogenesis . Open Biology . 3 . 7 . 130061 . July 2013 . 23864552 . 3728923 . 10.1098/rsob.130061 .
7. Poirier K, Keays DA, Francis F, Saillour Y, Bahi N, Manouvrier S, Fallet-Bianco C, Pasquier L, Toutain A, Tuy FP, Bienvenu T, Joriot S, Odent S, Ville D, Desguerre I, Goldenberg A, Moutard ML, Fryns JP, van Esch H, Harvey RJ, Siebold C, Flint J, Beldjord C, Chelly J . Large spectrum of lissencephaly and pachygyria phenotypes resulting from de novo missense mutations in tubulin alpha 1A (TUBA1A) . Human Mutation . 28 . 11 . 1055–1064 . November 2007 . 17584854 . 10.1002/humu.20572 . 22681290 . free .
8. Sapir T, Elbaum M, Reiner O . Reduction of microtubule catastrophe events by LIS1, platelet-activating factor acetylhydrolase subunit . The EMBO Journal . 16 . 23 . 6977–6984 . December 1997 . 9384577 . 1170301 . 10.1093/emboj/16.23.6977 .
9. Keays DA, Tian G, Poirier K, Huang GJ, Siebold C, Cleak J, Oliver PL, Fray M, Harvey RJ, Molnár Z, Piñon MC, Dear N, Valdar W, Brown SD, Davies KE, Rawlins JN, Cowan NJ, Nolan P, Chelly J, Flint J . Mutations in alpha-tubulin cause abnormal neuronal migration in mice and lissencephaly in humans . Cell . 128 . 1 . 45–57 . January 2007 . 17218254 . 1885944 . 10.1016/j.cell.2006.12.017 .
10. Löwe J, Li H, Downing KH, Nogales E . Refined structure of alpha beta-tubulin at 3.5 A resolution . Journal of Molecular Biology . 313 . 5 . 1045–1057 . November 2001 . 11700061 . 10.1006/jmbi.2001.5077 .