ID   TBB3_HUMAN              Reviewed;         450 AA.
AC   Q13509; Q9BTZ0; Q9BW10;
DT   15-JUL-1998, integrated into UniProtKB/Swiss-Prot.
DT   02-MAY-2002, sequence version 2.
DT   13-JUN-2012, entry version 116.
DE   RecName: Full=Tubulin beta-3 chain;
DE   AltName: Full=Tubulin beta-4 chain;
DE   AltName: Full=Tubulin beta-III;
GN   Name=TUBB3; Synonyms=TUBB4;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi;
OC   Mammalia; Eutheria; Euarchontoglires; Primates; Haplorrhini;
OC   Catarrhini; Hominidae; Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   MEDLINE=98146276; PubMed=9473684; DOI=10.1016/S0167-4781(97)00168-1;
RA   Ranganathan S., Dexter D.W., Benetatos C.A., Hudes G.R.;
RT   "Cloning and sequencing of human betaIII-tubulin cDNA: induction of
RT   betaIII isotype in human prostate carcinoma cells by acute exposure to
RT   antimicrotubule agents.";
RL   Biochim. Biophys. Acta 1395:237-245(1998).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Mammary cancer;
RA   Banerjee A.;
RL   Submitted (OCT-2001) to the EMBL/GenBank/DDBJ databases.
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   TISSUE=Lung;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA
RT   project: the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [4]
RP   PROTEIN SEQUENCE OF 63-77; 104-121; 242-251; 163-174 AND 381-390, AND
RP   MASS SPECTROMETRY.
RC   TISSUE=Brain, Cajal-Retzius cell, and Fetal brain cortex;
RA   Lubec G., Afjehi-Sadat L., Chen W.-Q., Sun Y.;
RL   Submitted (DEC-2008) to UniProtKB.
RN   [5]
RP   TISSUE SPECIFICITY.
RX   PubMed=14736079;
RA   Katsetos C.D., Legido A., Perentes E., Mork S.J.;
RT   "Class III beta-tubulin isotype: a key cytoskeletal protein at the
RT   crossroads of developmental neurobiology and tumor neuropathology.";
RL   J. Child Neurol. 18:851-866(2003).
RN   [6]
RP   ERRATUM.
RA   Katsetos C.D., Legido A., Perentes E., Mork S.J.;
RL   J. Child Neurol. 19:531-531(2004).
RN   [7]
RP   PHOSPHORYLATION AT SER-172 BY CDK1, AND MUTAGENESIS OF SER-172.
RX   PubMed=16371510; DOI=10.1091/mbc.E05-07-0621;
RA   Fourest-Lieuvin A., Peris L., Gache V., Garcia-Saez I.,
RA   Juillan-Binard C., Lantez V., Job D.;
RT   "Microtubule regulation in mitosis: tubulin phosphorylation by the
RT   cyclin-dependent kinase Cdk1.";
RL   Mol. Biol. Cell 17:1041-1050(2006).
RN   [8]
RP   GLYCYLATION.
RX   PubMed=19524510; DOI=10.1016/j.cell.2009.05.020;
RA   Rogowski K., Juge F., van Dijk J., Wloga D., Strub J.-M.,
RA   Levilliers N., Thomas D., Bre M.-H., Van Dorsselaer A., Gaertig J.,
RA   Janke C.;
RT   "Evolutionary divergence of enzymatic mechanisms for posttranslational
RT   polyglycylation.";
RL   Cell 137:1076-1087(2009).
RN   [9]
RP   ACETYLATION [LARGE SCALE ANALYSIS] AT LYS-58, AND MASS SPECTROMETRY.
RX   PubMed=19608861; DOI=10.1126/science.1175371;
RA   Choudhary C., Kumar C., Gnad F., Nielsen M.L., Rehman M., Walther T.,
RA   Olsen J.V., Mann M.;
RT   "Lysine acetylation targets protein complexes and co-regulates major
RT   cellular functions.";
RL   Science 325:834-840(2009).
RN   [10]
RP   FUNCTION, VARIANTS CFEOM3A GLN-62; CYS-262; HIS-262; THR-302; CYS-380;
RP   LYS-410; HIS-417 AND ASN-417, AND CHARACTERIZATION OF VARIANTS CFEOM3A
RP   GLN-62; CYS-262; HIS-262; THR-302; CYS-380 AND LYS-410.
RX   PubMed=20074521; DOI=10.1016/j.cell.2009.12.011;
RA   Tischfield M.A., Baris H.N., Wu C., Rudolph G., Van Maldergem L.,
RA   He W., Chan W.M., Andrews C., Demer J.L., Robertson R.L., Mackey D.A.,
RA   Ruddle J.B., Bird T.D., Gottlob I., Pieh C., Traboulsi E.I.,
RA   Pomeroy S.L., Hunter D.G., Soul J.S., Newlin A., Sabol L.J.,
RA   Doherty E.J., de Uzcategui C.E., de Uzcategui N., Collins M.L.,
RA   Sener E.C., Wabbels B., Hellebrand H., Meitinger T., de Berardinis T.,
RA   Magli A., Schiavi C., Pastore-Trossello M., Koc F., Wong A.M.,
RA   Levin A.V., Geraghty M.T., Descartes M., Flaherty M., Jamieson R.V.,
RA   Moller H.U., Meuthen I., Callen D.F., Kerwin J., Lindsay S.,
RA   Meindl A., Gupta M.L. Jr., Pellman D., Engle E.C.;
RT   "Human TUBB3 mutations perturb microtubule dynamics, kinesin
RT   interactions, and axon guidance.";
RL   Cell 140:74-87(2010).
RN   [11]
RP   TISSUE SPECIFICITY.
RX   PubMed=20191564; DOI=10.1002/cm.20436;
RA   Leandro-Garcia L.J., Leskela S., Landa I., Montero-Conde C.,
RA   Lopez-Jimenez E., Leton R., Cascon A., Robledo M.,
RA   Rodriguez-Antona C.;
RT   "Tumoral and tissue-specific expression of the major human beta-
RT   tubulin isotypes.";
RL   Cytoskeleton 67:214-223(2010).
RN   [12]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RX   PubMed=21269460; DOI=10.1186/1752-0509-5-17;
RA   Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P.,
RA   Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J.;
RT   "Initial characterization of the human central proteome.";
RL   BMC Syst. Biol. 5:17-17(2011).
RN   [13]
RP   VARIANTS CDCBM MET-178; LYS-205; VAL-302 AND VAL-323, AND
RP   CHARACTERIZATION OF VARIANTS CDCBM MET-178; LYS-205; VAL-302 AND
RP   VAL-323.
RX   PubMed=20829227; DOI=10.1093/hmg/ddq377;
RA   Poirier K., Saillour Y., Bahi-Buisson N., Jaglin X.H.,
RA   Fallet-Bianco C., Nabbout R., Castelnau-Ptakhine L., Roubertie A.,
RA   Attie-Bitach T., Desguerre I., Genevieve D., Barnerias C., Keren B.,
RA   Lebrun N., Boddaert N., Encha-Razavi F., Chelly J.;
RT   "Mutations in the neuronal ss-tubulin subunit TUBB3 result in
RT   malformation of cortical development and neuronal migration defects.";
RL   Hum. Mol. Genet. 19:4462-4473(2010).
CC   -!- FUNCTION: Tubulin is the major constituent of microtubules. It
CC       binds two moles of GTP, one at an exchangeable site on the beta
CC       chain and one at a non-exchangeable site on the alpha-chain. TUBB3
CC       plays a critical role in proper axon guidance and mantainance.
CC   -!- SUBUNIT: Dimer of alpha and beta chains.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytoskeleton.
CC   -!- TISSUE SPECIFICITY: Expression is primarily restricted to central
CC       and peripheral nervous system. Greatly increased expression in
CC       most cancerous tissues.
CC   -!- DOMAIN: The highly acidic C-terminal region may bind cations such
CC       as calcium.
CC   -!- PTM: Some glutamate residues at the C-terminus are
CC       polyglutamylated. This modification occurs exclusively on
CC       glutamate residues and results in polyglutamate chains on the
CC       gamma-carboxyl group. Also monoglycylated but not polyglycylated
CC       due to the absence of functional TTLL10 in human. Monoglycylation
CC       is mainly limited to tubulin incorporated into axonemes (cilia and
CC       flagella) whereas glutamylation is prevalent in neuronal cells,
CC       centrioles, axonemes, and the mitotic spindle. Both modifications
CC       can coexist on the same protein on adjacent residues, and lowering
CC       glycylation levels increases polyglutamylation, and reciprocally.
CC       The precise function of such modifications is still unclear but
CC       they regulate the assembly and dynamics of axonemal microtubules
CC       (Probable).
CC   -!- PTM: Phosphorylated on Ser-172 by CDK1 during the cell cycle, from
CC       metaphase to telophase, but not in interphase. This
CC       phosphorylation inhibits tubulin incorporation into microtubules.
CC   -!- DISEASE: Defects in TUBB3 are the cause of congenital fibrosis of
CC       extraocular muscles type 3A (CFEOM3A) [MIM:600638]. A congenital
CC       ocular motility disorder marked by restrictive ophthalmoplegia
CC       affecting extraocular muscles innervated by the oculomotor and/or
CC       trochlear nerves. It is clinically characterized by anchoring of
CC       the eyes in downward gaze, ptosis, and backward tilt of the head.
CC       Congenital fibrosis of extraocular muscles type 3 presents as a
CC       non-progressive, autosomal dominant disorder with variable
CC       expression. Patients may be bilaterally or unilaterally affected,
CC       and their oculo-motility defects range from complete
CC       ophthalmoplegia (with the eyes fixed in a hypo- and exotropic
CC       position), to mild asymptomatic restrictions of ocular movement.
CC       Ptosis, refractive error, amblyopia, and compensatory head
CC       positions are associated with the more severe forms of the
CC       disorder. In some cases the ocular phenotype is accompanied by
CC       additional features including developmental delay, corpus callosum
CC       agenesis, basal ganglia dysmorphism, facial weakness,
CC       polyneuropathy.
CC   -!- DISEASE: Defects in TUBB3 are the cause of cortical dysplasia
CC       complex with other brain malformations (CDCBM) [MIM:614039]. CDCBM
CC       is a disorder of aberrant neuronal migration and disturbed axonal
CC       guidance. Affected individuals have mild to severe mental
CC       retardation, strabismus, axial hypotonia, and spasticity. Brain
CC       imaging shows variable malformations of cortical development,
CC       including polymicrogyria, gyral disorganization, and fusion of the
CC       basal ganglia, as well as thin corpus callosum, hypoplastic
CC       brainstem, and dysplastic cerebellar vermis. Extraocular muscles
CC       are not involved.
CC   -!- SIMILARITY: Belongs to the tubulin family.
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DR   EMBL; U47634; AAC52035.1; -; mRNA.
DR   EMBL; AF427491; AAL28094.1; -; mRNA.
DR   EMBL; BC000748; AAH00748.1; -; mRNA.
DR   EMBL; BC003021; AAH03021.2; -; mRNA.
DR   IPI; IPI00013683; -.
DR   RefSeq; NP_001184110.1; NM_001197181.1.
DR   RefSeq; NP_006077.2; NM_006086.3.
DR   UniGene; Hs.511743; -.
DR   ProteinModelPortal; Q13509; -.
DR   SMR; Q13509; 2-427.
DR   IntAct; Q13509; 6.
DR   MINT; MINT-1163245; -.
DR   STRING; Q13509; -.
DR   PhosphoSite; Q13509; -.
DR   DMDM; 20455526; -.
DR   OGP; Q13509; -.
DR   PRIDE; Q13509; -.
DR   DNASU; 10381; -.
DR   Ensembl; ENST00000315491; ENSP00000320295; ENSG00000198211.
DR   GeneID; 10381; -.
DR   KEGG; hsa:10381; -.
DR   UCSC; uc002fpf.2; human.
DR   CTD; 10381; -.
DR   GeneCards; GC16P089987; -.
DR   HGNC; HGNC:20772; TUBB3.
DR   HPA; CAB011512; -.
DR   MIM; 600638; phenotype.
DR   MIM; 602661; gene.
DR   MIM; 614039; phenotype.
DR   neXtProt; NX_Q13509; -.
DR   Orphanet; 45358; Congenital fibrosis of extraocular muscles.
DR   PharmGKB; PA134953867; -.
DR   GeneTree; ENSGT00650000092923; -.
DR   HOGENOM; HOG000165710; -.
DR   HOVERGEN; HBG000089; -.
DR   KO; K07375; -.
DR   Reactome; REACT_111045; Developmental Biology.
DR   Reactome; REACT_11123; Membrane Trafficking.
DR   Reactome; REACT_115566; Cell Cycle.
DR   Reactome; REACT_17015; Metabolism of proteins.
DR   Reactome; REACT_383; DNA Replication.
DR   Reactome; REACT_604; Hemostasis.
DR   NextBio; 39327; -.
DR   ArrayExpress; Q13509; -.
DR   CleanEx; HS_TUBB3; -.
DR   CleanEx; HS_TUBB4; -.
DR   Genevestigator; Q13509; -.
DR   GermOnline; ENSG00000198211; Homo sapiens.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-KW.
DR   GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR   GO; GO:0005525; F:GTP binding; IEA:UniProtKB-KW.
DR   GO; GO:0003924; F:GTPase activity; IEA:InterPro.
DR   GO; GO:0005198; F:structural molecule activity; IEA:InterPro.
DR   GO; GO:0051084; P:'de novo' posttranslational protein folding; TAS:Reactome.
DR   GO; GO:0007411; P:axon guidance; IMP:UniProtKB.
DR   GO; GO:0007018; P:microtubule-based movement; IEA:InterPro.
DR   GO; GO:0051258; P:protein polymerization; IEA:InterPro.
DR   Gene3D; G3DSA:3.30.1330.20; Tubulin/FtsZ_2-layer-sand-dom; 1.
DR   Gene3D; G3DSA:1.10.287.600; Tubulin_C; 1.
DR   Gene3D; G3DSA:3.40.50.1440; Tubulin_FtsZ; 1.
DR   InterPro; IPR013838; Beta-tubulin_BS.
DR   InterPro; IPR002453; Beta_tubulin.
DR   InterPro; IPR008280; Tub_FtsZ_C.
DR   InterPro; IPR000217; Tubulin.
DR   InterPro; IPR018316; Tubulin/FtsZ_2-layer-sand-dom.
DR   InterPro; IPR023123; Tubulin_C.
DR   InterPro; IPR017975; Tubulin_CS.
DR   InterPro; IPR003008; Tubulin_FtsZ_GTPase.
DR   Pfam; PF00091; Tubulin; 1.
DR   Pfam; PF03953; Tubulin_C; 1.
DR   PRINTS; PR01163; BETATUBULIN.
DR   PRINTS; PR01161; TUBULIN.
DR   SMART; SM00864; Tubulin; 1.
DR   SMART; SM00865; Tubulin_C; 1.
DR   SUPFAM; SSF55307; Tub_FtsZ_C; 1.
DR   SUPFAM; SSF52490; Tubulin_FtsZ; 1.
DR   PROSITE; PS00227; TUBULIN; 1.
DR   PROSITE; PS00228; TUBULIN_B_AUTOREG; 1.
PE   1: Evidence at protein level;
KW   Acetylation; Complete proteome; Cytoplasm; Cytoskeleton;
KW   Direct protein sequencing; Disease mutation; GTP-binding; Microtubule;
KW   Nucleotide-binding; Phosphoprotein; Reference proteome.
FT   CHAIN         1    450       Tubulin beta-3 chain.
FT                                /FTId=PRO_0000048250.
FT   NP_BIND     140    146       GTP (Potential).
FT   MOD_RES      58     58       N6-acetyllysine.
FT   MOD_RES     172    172       Phosphoserine; by CDK1.
FT   VARIANT      62     62       R -> Q (in CFEOM3A; affects heterodimers
FT                                formation; results in increased stability
FT                                and reduced dynamics of microtubules).
FT                                /FTId=VAR_062758.
FT   VARIANT     178    178       T -> M (in CDCBM; can form tubulin
FT                                heterodimers that are properly
FT                                incorporated into microtubules; the
FT                                microtubules are less stable than wild-
FT                                type).
FT                                /FTId=VAR_066206.
FT   VARIANT     205    205       E -> K (in CDCBM; does not form tubulin
FT                                heterodimers; patient fibroblasts show no
FT                                major alterations in the microtubule
FT                                network, but the microtubules are less
FT                                stable than wild-type).
FT                                /FTId=VAR_066207.
FT   VARIANT     262    262       R -> C (in CFEOM3A; affects heterodimers
FT                                formation; affects microtubules
FT                                polymerization and depolymerization
FT                                rates).
FT                                /FTId=VAR_062759.
FT   VARIANT     262    262       R -> H (in CFEOM3A; severe phenotype with
FT                                congenital facial weakness, congenital
FT                                wrist and finger contractures; affects
FT                                microtubules polymerization and
FT                                depolymerization rates).
FT                                /FTId=VAR_062760.
FT   VARIANT     302    302       A -> T (in CFEOM3A; affects heterodimers
FT                                formation; results in increased stability
FT                                and reduced dynamics of microtubules).
FT                                /FTId=VAR_062761.
FT   VARIANT     302    302       A -> V (in CDCBM; does not form tubulin
FT                                heterodimers).
FT                                /FTId=VAR_066208.
FT   VARIANT     323    323       M -> V (in CDCBM; reduced heterodimers
FT                                formation).
FT                                /FTId=VAR_066209.
FT   VARIANT     380    380       R -> C (in CFEOM3A; affects heterodimers
FT                                formation; results in increased stability
FT                                and reduced dynamics of microtubules).
FT                                /FTId=VAR_062762.
FT   VARIANT     410    410       E -> K (in CFEOM3A; severe phenotype with
FT                                congenital facial weakness; lower
FT                                extremity weakness and sensory loss in
FT                                the second to third decade of life in one
FT                                patient; affects microtubules
FT                                polymerization and depolymerization
FT                                rates).
FT                                /FTId=VAR_062763.
FT   VARIANT     417    417       D -> H (in CFEOM3A; severe phenotype with
FT                                congenital facial weakness, congenital
FT                                wrist and finger contractures).
FT                                /FTId=VAR_062764.
FT   VARIANT     417    417       D -> N (in CFEOM3A; some patients with
FT                                lower extremity weakness and sensory loss
FT                                in the second to third decade of life;
FT                                also found in patients without CFEOM3A
FT                                who developed polyneuropathy).
FT                                /FTId=VAR_062765.
FT   MUTAGEN     172    172       S->A: Loss of CDK1-mediated
FT                                phosphorylation.
FT   MUTAGEN     172    172       S->D,E: Mimics phosphorylation, unable to
FT                                incorporate into microtubules.
FT   CONFLICT    275    275       A -> R (in Ref. 1; AAC52035).
SQ   SEQUENCE   450 AA;  50433 MW;  4B9CDE7DBA102949 CRC64;
     MREIVHIQAG QCGNQIGAKF WEVISDEHGI DPSGNYVGDS DLQLERISVY YNEASSHKYV
     PRAILVDLEP GTMDSVRSGA FGHLFRPDNF IFGQSGAGNN WAKGHYTEGA ELVDSVLDVV
     RKECENCDCL QGFQLTHSLG GGTGSGMGTL LISKVREEYP DRIMNTFSVV PSPKVSDTVV
     EPYNATLSIH QLVENTDETY CIDNEALYDI CFRTLKLATP TYGDLNHLVS ATMSGVTTSL
     RFPGQLNADL RKLAVNMVPF PRLHFFMPGF APLTARGSQQ YRALTVPELT QQMFDAKNMM
     AACDPRHGRY LTVATVFRGR MSMKEVDEQM LAIQSKNSSY FVEWIPNNVK VAVCDIPPRG
     LKMSSTFIGN STAIQELFKR ISEQFTAMFR RKAFLHWYTG EGMDEMEFTE AESNMNDLVS
     EYQQYQDATA EEEGEMYEDD EEESEAQGPK
//