Interaction of TPPP/p25 protein with glyceraldehyde‐3‐phosphate dehydrogenase and their co‐localization in Lewy bodies

Oláh, Judit; Tõkési, Natália; Vincze, Orsolya; Horváth, István; Lehotzky, Attila; Erdei, Anna; Szájli, Emília; Medzihradszky, Katalin F.; Orosz, Ferenc; Kovács, Gábor G.; Ovádi, Judit

doi:10.1016/j.febslet.2006.09.037

Cited by 36 publications

(24 citation statements)

References 25 publications

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“…the oligodendroglial cytoplasm and all oligodendroglial processes [7,8], two studies previously reported that TPPP is localized in the nucleus [10,20], consistent with the present data. Höftberger and colleagues previously analyzed the localization of TPPP in the human brain by immunohistochemistry and immunoelectron microscopy, and showed that TPPP was localized in oligodendroglial nuclei as well as its cytoplasm [10].…”

Section: Discussionsupporting

confidence: 81%

“…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%

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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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Section: Discussionsupporting

confidence: 81%

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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“…4A shows the proteins that were bound to the affinity column, and then eluted by 0.5 M NaCl. The two dominant bands in the gel correspond to tubulin and GAPDH as reported earlier (6). Between these two bands the marked band was excised and in-gel digested with trypsin.…”

Section: Resultsmentioning

confidence: 99%

“…Affinity Chromatography-Human recombinant TPPP was immobilized to CNBr-activated Sepharose 4B (Amersham Biosciences) and used for finding interacting proteins from bovine brain extract as described previously (6). The bound proteins were eluted with 10 mM phosphate buffer, pH 7.0, containing 0.5 M NaCl, and the protein bands obtained by SDS-PAGE (19) were analyzed by mass spectrometry.…”

Section: Methodsmentioning

confidence: 99%

Phosphorylation Blocks the Activity of Tubulin Polymerization-promoting Protein (TPPP)

Hlavanda

Klement

Kókai

et al. 2007

Journal of Biological Chemistry

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109

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Tubulin polymerization-promoting protein (TPPP), an unfolded brain-specific protein interacts with the tubulin/microtubule system in vitro and in vivo, and is enriched in human pathological brain inclusions. Here we show that TPPP induces tubulin self-assembly into intact frequently bundled microtubules, and that the phosphorylation of specific sites distinctly affects the function of TPPP. In vitro phosphorylation of wild type and the truncated form (⌬3-43TPPP) of human recombinant TPPP was performed by kinases involved in brain-specific processes. A stoichiometry of 2.9 ؎ 0.3, 2.2 ؎ 0.3, and 0.9 ؎ 0.1 mol P/mol protein with ERK2, cyclin-dependent kinase 5 (Cdk5), and cAMP-dependent protein kinase (PKA), respectively, was revealed for the full-length protein, and 0.4 -0.5 mol P/mol protein was detected with all three kinases when the N-terminal tail was deleted. The phosphorylation sites Thr 14 , Ser 18 , Ser 160 for Cdk5; Ser 18 , Ser 160 for ERK2, and Ser 32 for PKA were identified by mass spectrometry. These sites were consistent with the bioinformatic predictions. The three N-terminal sites were also found to be phosphorylated in vivo in TPPP isolated from bovine brain. Affinity binding experiments provided evidence for the direct interaction between TPPP and ERK2. Previously we isolated a new, flexible, intrinsically unstructured protein from bovine brain, which was denoted tubulin polymerization-promoting protein (TPPP) 3 /p25 accordingly to its in vitro function, tubulin polymerizationpromoting protein, and its molecular mass (1). In the HGNC data base this protein is assigned as TPPP, the first member of TPPP family. We have shown that TPPP can induce formation of double-walled microtubules (MTs) and aberrant tubulin aggregates (2) as well as that it stabilizes MT network via its bundling activity in human cells (3). There are two TPPP homologues, p18 (TPPP2) and p20 (TPPP3) with distinct structural and functional features concerning their folding and tubulin binding properties (4). The physiological functions of the TPPP protein family are unknown; however, TPPP has been suggested to take part in the stabilization of the MT network (3).Both ␣-synuclein and GAPDH directly bind to TPPP and co-localize in the Lewy body (5-7). Our immunohistochemistry studies revealed enrichment of TPPP in ␣-synuclein-positive inclusions characteristic for synucleinopathies but not for tauopathies (5). TPPP is similar to ␣-synuclein and tau (2,8) as far as all of them belong to the family of the unstructured proteins.Protein phosphorylation has a significant impact in the etiology of neurodegenerative processes (9). For example, tau and ␣-synuclein, the major hallmarks of Parkinson and Alzheimer diseases, respectively, are targets of different protein kinases. One of the kinases phosphorylating tau with pathological relevance in Alzheimer disease is cyclin-dependent kinase 5 (Cdk5), which is abundant in brain tissue, associates with tau (10), and plays important role in the signaling of mitogen-activated protein kinases ...

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“…GAPDH and Hsp90 only interacted with the FKBP36 affinity matrix, whereas no binding was observed to the matrix alone. The FKBP36 TPR Domain Binds GAPDH and Hsp90-To test whether FKBP36 binds directly to GAPDH, we made use of purified GAPDH from rabbit muscle, which was previously utilized in several similar studies (11)(12)(13). Isolated GAPDH was incubated with the GST-FKBP36 affinity matrix.…”

Section: Fkbp36mentioning

confidence: 99%

FKBP36 Is an Inherent Multifunctional Glyceraldehyde-3-phosphate Dehydrogenase Inhibitor

Jarczowski

Jahreis

Erdmann

et al. 2009

Journal of Biological Chemistry

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FKBP36 has been previously shown to be a crucial factor in spermatogenesis because of its interplay with the synaptonemal complex protein SCPI. Here we show that beyond this function, FKBP36 forms complexes with glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1.12) and Hsp90. Both proteins bind independently to different sites of the FKBP36 tetratricopeptide repeat domain. The interaction between FKBP36 and GAPDH directly inhibits the catalytic activity of GAPDH. In addition, FKBP36 expression causes a significant reduction of the GAPDH level and activity in COS-7 cells. Particularly in the cytosolic fraction, GAPDH was depleted by FKBP36 expression. Thus, FKBP36 diminishes GAPDH activity by direct interaction and down-regulation of GAPDH, which represents a previously unknown mechanism of GAPDH regulation and a novel function of FKBP36 in testis-specific signaling.FKBP36 (FK506-binding protein 36; FKBP6) belongs to the human immunophilins and is predominantly found in testes. FKBP6 was initially identified as one of the genes on chromosome 7 whose deletion is linked to Williams-Beuren syndrome (1). Williams-Beuren syndrome is a dominant autosomal disorder, which may include supravalvular aortic stenosis, multiple peripheral pulmonary arterial stenoses, elfin face, mental and statural deficiency, characteristic dental malformation, and infantile hypercalcemia (2).FKBP36 is predominantly expressed in testes and plays an important role in spermatogenesis. The loss of FKBP36 causes a significant reduction of the size of testes and the infertility of male mice. The testis-specific FKBP was identified as a component of the synaptonemal complex, which forms between two homologous chromosomes during meiosis (3). The synaptonemal complex participates in chromosome pairing, synapsis, and recombination (4).FKBP36 contains an N-terminal peptidyl-prolyl cis/trans isomerase domain and three tetratricopeptide repeat (TPR) 3 motifs in its C-terminal segment. Furthermore, FKBP36 displays a high sequence homology to the regulated FKBP38, and the absence of FKBP36 activity might suggest a similar activation scenario (5). The TPR domains of FKBP38, FKBP51, and FKBP52 have been shown to interact with the heat shock protein Hsp90 (5, 6). The interactions between the different FKBPs and Hsp90 are mediated by the Hsp90 C90 domain. Complexes of FKBP51 and FKBP52 with Hsp90 have been reported to interact with client molecules, e.g. steroid hormone receptors, to modify the activity, stability, or subcellular localization of the client proteins (7). Within these complexes, the FKBPs interact with both the receptor and Hsp90 (8).In the present study, we show that FKBP36 interacts with Hsp90 via the TPR domain. A second binding site in the TPR domain of FKBP36 mediates the interaction with GAPDH, leading to GAPDH-FKBP36-Hsp90 complexes, which are comparable to complexes formed by other TPR-containing immunophilins. Furthermore, our experiments showed that FKBP36 controls GAPDH activity either by direct interference with binding of t...

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Interaction of TPPP/p25 protein with glyceraldehyde‐3‐phosphate dehydrogenase and their co‐localization in Lewy bodies

Cited by 36 publications

References 25 publications

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

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

Phosphorylation Blocks the Activity of Tubulin Polymerization-promoting Protein (TPPP)

FKBP36 Is an Inherent Multifunctional Glyceraldehyde-3-phosphate Dehydrogenase Inhibitor

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