An unstructured protein with destructive potential: TPPP/p25 in neurodegeneration

Ovádi, Judit; Orosz, Ferenc

doi:10.1002/bies.200900008

Cited by 46 publications

(33 citation statements)

References 70 publications

(123 reference statements)

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“…Thus, our results underline the previously proposed view, namely that the microtubules could not be stabilized by acetylation itself; rather other mechanisms could be responsible for this, and these stable microtubules then accumulate acetylated tubulins (22,40). We propose that the expression of TPPP/p25, as a MAP (7,41), could be a factor that induces the stabilization of the microtubule network via its bundling activity.…”

Section: Discussionsupporting

confidence: 85%

TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6

Tõkési

Lehotzky

Horváth

et al. 2010

Journal of Biological Chemistry

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109

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TPPP/p25 (tubulin polymerization-promoting protein/p25) is an unstructured protein that induces microtubule polymerization in vitro and is aligned along the microtubule network in transfected mammalian cells. In normal human brain, TPPP/ p25 is expressed predominantly in oligodendrocytes, where its expression is proved to be crucial for their differentiation process. Here we demonstrated that the expression of TPPP/p25 in HeLa cells, in doxycycline-inducible CHO10 cells, and in the oligodendrocyte CG-4 cells promoted the acetylation of ␣-tubulin at residue Lys-40, whereas its down-regulation by specific small interfering RNA in CG-4 cells or by the withdrawal of doxycycline from CHO10 cells decreased the acetylation level of ␣-tubulin. Our results indicate that TPPP/p25 binds to HDAC6 (histone deacetylase 6), an enzyme responsible for tubulin deacetylation. Moreover, we demonstrated that the direct interaction of these two proteins resulted in the inhibition of the deacetylase activity of HDAC6. The measurement of HDAC6 activity showed that TPPP/p25 is able to induce almost complete (90%) inhibition at 3 M concentration. In addition, treatment of the cells with nocodazole, vinblastine, or cold exposure revealed that microtubule acetylation induced by trichostatin A, a well known HDAC6 inhibitor, does not cause microtubule stabilization. In contrast, the microtubule bundling activity of TPPP/p25 was able to protect the microtubules from depolymerization. Finally, we demonstrated that, similarly to other HDAC6 inhibitors, TPPP/p25 influences the microtubule dynamics by decreasing the growth velocity of the microtubule plus ends and also affects cell motility as demonstrated by time lapse video experiments. Thus, we suggest that TPPP/p25 is a multiple effector of the microtubule organization.

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Section: Discussionsupporting

confidence: 85%

TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6

Tõkési

Lehotzky

Horváth

et al. 2010

Journal of Biological Chemistry

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109

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“…Intracellular TPPP/p25 levels influence cell differentiation and proliferation and might be implicated in Parkinson's disease and other nervous system pathologies [72]. The TPPP/p25 amino acid sequence exhibits characteristics typical of IDPs [72]; CD measurements attest to extensive random-coil structure [73], whereas 1D and 2D NMR spectra indicate multiple protein conformations and increased protein flexibility [28,74]. Extended disordered segments are located primarily at the N-and C-termini, but the mid-region also exhibits high flexibility.…”

Section: +mentioning

confidence: 99%

Protein Conformational Disorder and Enzyme Catalysis

Schulenburg

Hilvert

2013

Topics in Current Chemistry

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Though lacking a well-defined three-dimensional structure, intrinsically unstructured proteins are ubiquitous in nature. These molecules play crucial roles in many cellular processes, especially signaling and regulation. Surprisingly, even enzyme catalysis can tolerate substantial disorder. This observation contravenes conventional wisdom but is relevant to an understanding of how protein dynamics modulates enzyme function. This chapter reviews properties and characteristics of disordered proteins, emphasizing examples of enzymes that lack defined structures, and considers implications of structural disorder for catalytic efficiency and evolution.

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“…TPPP is also essential for the reorganization and stabilization of microtubules [2,5]. Another characteristic biochemical feature of TPPP is that it normally remains as an unfolded and unstructured protein without binding partners [6], whereas in the presence of proteins such as myelin basic protein (MBP) or tubulin [2,[7][8][9], it changes its secondary structure and exerts physiological roles such as binding with tubulin to stabilize microtubules [2,5]. TPPP is also a guanosine triphosphate (GTP)-binding protein, which hydrolyzes GTP to produce guanosine diphosphate (GDP), and participates in multiple physiological functions [9].…”

Section: Introductionmentioning

confidence: 99%

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

Ota

Obayashi

Ozaki

et al. 2014

Acta Neuropathologica Communications

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Abstractp25α/tubulin polymerization promoting protein (TPPP) is an oligodendroglial protein that plays crucial roles including myelination, and the stabilization of microtubules. In multiple system atrophy (MSA), TPPP is suggested to relocate from the myelin sheath to the oligodendroglial cell body, before the formation of glial cytoplasmic inclusions (GCIs), the pathologic hallmark of MSA. However, much is left unknown about the re-distribution of TPPP in MSA. We generated new antibodies against the N-and C-terminus of TPPP, and analyzed control and MSA brains, including the brain of a familial MSA patient carrying homozygous mutations in the coenzyme Q2 gene (COQ2). In control brain tissues, TPPP was localized not only in the cytoplasmic component of the oligodendroglia including perinuclear cytoplasm and peripheral processes in the white matter, but also in the nucleus of a fraction (62.4%) of oligodendroglial cells. Immunoelectron microscopic analysis showed TPPP in the nucleus and mitochondrial membrane of normal oligodendroglia, while western blot also supported its nuclear and mitochondrial existence. In MSA, the prevalence of nuclear TPPP was 48.6% in the oligodendroglia lacking GCIs, whereas it was further decreased to 19.6% in the oligodendroglia with phosphorylated α-synuclein (pα-syn)-positive GCIs, both showing a significant decrease compared to controls (62.4%). In contrast, TPPP accumulated in the perinuclear cytoplasm where mitochondrial membrane (TOM20 and cytochrome C) and fission (DRP1) proteins were often immunoreactive. We conclude that in MSA-oligodendroglia, TPPP is reduced, not only in the peripheral cytoplasm, but also in the nucleus and relocated to the perinuclear cytoplasm.

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An unstructured protein with destructive potential: TPPP/p25 in neurodegeneration

Cited by 46 publications

References 70 publications

TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6

TPPP/p25 Promotes Tubulin Acetylation by Inhibiting Histone Deacetylase 6

Protein Conformational Disorder and Enzyme Catalysis

Relocation of p25¿/tubulin polymerization promoting protein from the nucleus to the perinuclear cytoplasm in the oligodendroglia of sporadic and COQ2 mutant multiple system atrophy

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