9j4d

Structural highlights

Function

TPPP_HUMAN Regulator of microtubule dynamics that plays a key role in myelination by promoting elongation of the myelin sheath (PubMed:31522887). Acts as a microtubule nucleation factor in oligodendrocytes: specifically localizes to the postsynaptic Golgi apparatus region, also named Golgi outpost, and promotes microtubule nucleation, an important step for elongation of the myelin sheath (PubMed:31522887, PubMed:33831707). Required for both uniform polarized growth of distal microtubules as well as directing the branching of proximal processes (PubMed:31522887). Shows magnesium-dependent GTPase activity; the role of the GTPase activity is unclear (PubMed:21316364, PubMed:21995432). In addition to microtubule nucleation activity, also involved in microtubule bundling and stabilization of existing microtubules, thereby maintaining the integrity of the microtubule network (PubMed:17105200, PubMed:17693641, PubMed:18028908, PubMed:26289831). Regulates microtubule dynamics by promoting tubulin acetylation: acts by inhibiting the tubulin deacetylase activity of HDAC6 (PubMed:20308065, PubMed:23093407). Also regulates cell migration: phosphorylation by ROCK1 inhibits interaction with HDAC6, resulting in decreased acetylation of tubulin and increased cell motility (PubMed:23093407). Plays a role in cell proliferation by regulating the G1/S-phase transition (PubMed:23355470). Involved in astral microtubule organization and mitotic spindle orientation during early stage of mitosis; this process is regulated by phosphorylation by LIMK2 (PubMed:22328514).^{[1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11]}

References

1. ↑ Vincze O, Tokesi N, Olah J, Hlavanda E, Zotter A, Horvath I, Lehotzky A, Tirian L, Medzihradszky KF, Kovacs J, Orosz F, Ovadi J. Tubulin polymerization promoting proteins (TPPPs): members of a new family with distinct structures and functions. Biochemistry. 2006 Nov 21;45(46):13818-26. PMID:17105200 doi:http://dx.doi.org/10.1021/bi061305e
2. ↑ Hlavanda E, Klement E, Kókai E, Kovács J, Vincze O, Tökési N, Orosz F, Medzihradszky KF, Dombrádi V, Ovádi J. Phosphorylation blocks the activity of tubulin polymerization-promoting protein (TPPP): identification of sites targeted by different kinases. J Biol Chem. 2007 Oct 5;282(40):29531-9. PMID:17693641 doi:10.1074/jbc.M703466200
3. ↑ Acevedo K, Li R, Soo P, Suryadinata R, Sarcevic B, Valova VA, Graham ME, Robinson PJ, Bernard O. The phosphorylation of p25/TPPP by LIM kinase 1 inhibits its ability to assemble microtubules. Exp Cell Res. 2007 Dec 10;313(20):4091-106. PMID:18028908 doi:10.1016/j.yexcr.2007.08.012
4. ↑ Tokési N, Lehotzky A, Horváth I, Szabó B, Oláh J, Lau P, Ovádi J. TPPP/p25 promotes tubulin acetylation by inhibiting histone deacetylase 6. J Biol Chem. 2010 Jun 4;285(23):17896-906. PMID:20308065 doi:10.1074/jbc.M109.096578
5. ↑ Zotter A, Bodor A, Oláh J, Hlavanda E, Orosz F, Perczel A, Ovádi J. Disordered TPPP/p25 binds GTP and displays Mg2+-dependent GTPase activity. FEBS Lett. 2011 Mar 9;585(5):803-8. PMID:21316364 doi:10.1016/j.febslet.2011.02.006
6. ↑ Zotter Á, Oláh J, Hlavanda E, Bodor A, Perczel A, Szigeti K, Fidy J, Ovádi J. Zn²+-induced rearrangement of the disordered TPPP/p25 affects its microtubule assembly and GTPase activity. Biochemistry. 2011 Nov 8;50(44):9568-78. PMID:21995432 doi:10.1021/bi201447w
7. ↑ Heng YW, Lim HH, Mina T, Utomo P, Zhong S, Lim CT, Koh CG. TPPP acts downstream of RhoA-ROCK-LIMK2 to regulate astral microtubule organization and spindle orientation. J Cell Sci. 2012 Mar 15;125(Pt 6):1579-90. PMID:22328514 doi:10.1242/jcs.096818
8. ↑ Schofield AV, Steel R, Bernard O. Rho-associated coiled-coil kinase (ROCK) protein controls microtubule dynamics in a novel signaling pathway that regulates cell migration. J Biol Chem. 2012 Dec 21;287(52):43620-9. PMID:23093407 doi:10.1074/jbc.M112.394965
9. ↑ Schofield AV, Gamell C, Suryadinata R, Sarcevic B, Bernard O. Tubulin polymerization promoting protein 1 (Tppp1) phosphorylation by Rho-associated coiled-coil kinase (rock) and cyclin-dependent kinase 1 (Cdk1) inhibits microtubule dynamics to increase cell proliferation. J Biol Chem. 2013 Mar 15;288(11):7907-7917. PMID:23355470 doi:10.1074/jbc.M112.441048
10. ↑ DeBonis S, Neumann E, Skoufias DA. Self protein-protein interactions are involved in TPPP/p25 mediated microtubule bundling. Sci Rep. 2015 Aug 20;5:13242. PMID:26289831 doi:10.1038/srep13242
11. ↑ Fu MM, McAlear TS, Nguyen H, Oses-Prieto JA, Valenzuela A, Shi RD, Perrino JJ, Huang TT, Burlingame AL, Bechstedt S, Barres BA. The Golgi Outpost Protein TPPP Nucleates Microtubules and Is Critical for Myelination. Cell. 2019 Sep 19;179(1):132-146.e14. PMID:31522887 doi:10.1016/j.cell.2019.08.025