9m1l

Structural highlights

Disease

TBCD_HUMAN Early-onset progressive diffuse brain atrophy-microcephaly-muscle weakness-optic atrophy syndrome. The disease is caused by variants affecting the gene represented in this entry.

Function

TBCD_HUMAN Tubulin-folding protein implicated in the first step of the tubulin folding pathway and required for tubulin complex assembly. Involved in the regulation of microtubule polymerization or depolymerization, it modulates microtubule dynamics by capturing GTP-bound beta-tubulin (TUBB). Its ability to interact with beta tubulin is regulated via its interaction with ARL2. Acts as a GTPase-activating protein (GAP) for ARL2. Induces microtubule disruption in absence of ARL2. Increases degradation of beta tubulin, when overexpressed in polarized cells. Promotes epithelial cell detachment, a process antagonized by ARL2. Induces tight adherens and tight junctions disassembly at the lateral cell membrane (PubMed:10722852, PubMed:10831612, PubMed:11847227, PubMed:20740604, PubMed:27666370, PubMed:28158450). Required for correct assembly and maintenance of the mitotic spindle, and proper progression of mitosis (PubMed:27666370). Involved in neuron morphogenesis (PubMed:27666374).^{[1] [2] [3] [4] [5] [6] [7]}

References

1. ↑ Martín L, Fanarraga ML, Aloria K, Zabala JC. Tubulin folding cofactor D is a microtubule destabilizing protein. FEBS Lett. 2000 Mar 17;470(1):93-5. PMID:10722852 doi:10.1016/s0014-5793(00)01293-x
2. ↑ Bhamidipati A, Lewis SA, Cowan NJ. ADP ribosylation factor-like protein 2 (Arl2) regulates the interaction of tubulin-folding cofactor D with native tubulin. J Cell Biol. 2000 May 29;149(5):1087-96. PMID:10831612
3. ↑ Bartolini F, Bhamidipati A, Thomas S, Schwahn U, Lewis SA, Cowan NJ. Functional overlap between retinitis pigmentosa 2 protein and the tubulin-specific chaperone cofactor C. J Biol Chem. 2002 Apr 26;277(17):14629-34. Epub 2002 Feb 14. PMID:11847227 doi:10.1074/jbc.M200128200
4. ↑ Tian G, Thomas S, Cowan NJ. Effect of TBCD and its regulatory interactor Arl2 on tubulin and microtubule integrity. Cytoskeleton (Hoboken). 2010 Nov;67(11):706-14. doi: 10.1002/cm.20480. PMID:20740604 doi:http://dx.doi.org/10.1002/cm.20480
5. ↑ Flex E, Niceta M, Cecchetti S, Thiffault I, Au MG, Capuano A, Piermarini E, Ivanova AA, Francis JW, Chillemi G, Chandramouli B, Carpentieri G, Haaxma CA, Ciolfi A, Pizzi S, Douglas GV, Levine K, Sferra A, Dentici ML, Pfundt RR, Le Pichon JB, Farrow E, Baas F, Piemonte F, Dallapiccola B, Graham JM Jr, Saunders CJ, Bertini E, Kahn RA, Koolen DA, Tartaglia M. Biallelic Mutations in TBCD, Encoding the Tubulin Folding Cofactor D, Perturb Microtubule Dynamics and Cause Early-Onset Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):962-973. PMID:27666370 doi:10.1016/j.ajhg.2016.08.003
6. ↑ Miyake N, Fukai R, Ohba C, Chihara T, Miura M, Shimizu H, Kakita A, Imagawa E, Shiina M, Ogata K, Okuno-Yuguchi J, Fueki N, Ogiso Y, Suzumura H, Watabe Y, Imataka G, Leong HY, Fattal-Valevski A, Kramer U, Miyatake S, Kato M, Okamoto N, Sato Y, Mitsuhashi S, Nishino I, Kaneko N, Nishiyama A, Tamura T, Mizuguchi T, Nakashima M, Tanaka F, Saitsu H, Matsumoto N. Biallelic TBCD Mutations Cause Early-Onset Neurodegenerative Encephalopathy. Am J Hum Genet. 2016 Oct 6;99(4):950-961. PMID:27666374 doi:10.1016/j.ajhg.2016.08.005
7. ↑ Edvardson S, Tian G, Cullen H, Vanyai H, Ngo L, Bhat S, Aran A, Daana M, Da'amseh N, Abu-Libdeh B, Cowan NJ, Heng JI, Elpeleg O. Infantile neurodegenerative disorder associated with mutations in TBCD, an essential gene in the tubulin heterodimer assembly pathway. Hum Mol Genet. 2016 Nov 1;25(21):4635-4648. PMID:28158450 doi:10.1093/hmg/ddw292