title: Zinc-induced structural changes of the disordered tppp/p25 inhibits its degradation by the proteasome.
abstract: Tubulin Polymerization Promoting Protein/p25 (TPPP/p25), a neomorphic moonlighting protein displaying both physiological and pathological functions, plays a crucial role in the differentiation of the zinc-rich oligodendrocytes, the major constituent of myelin sheath; and it is enriched and co-localizes with α-synuclein in brain inclusions hallmarking Parkinson's disease and other synucleinopathies. In this work we showed that the binding of Zn(2+) to TPPP/p25 promotes its dimerization resulting in increased tubulin polymerization promoting activity. We also demonstrated that the Zn(2+) increases the intracellular TPPP/p25 level resulting in a more decorated microtubule network in CHO10 and CG-4 cells expressing TPPP/p25 ectopically and endogenously, respectively. This stabilization effect is crucial for the differentiation and aggresome formation under physiological and pathological conditions, respectively. The Zn(2+)-mediated effect was similar to that produced by treatment of the cells with MG132, a proteasome inhibitor or Zn(2+) plus MG132 as quantified by cellular ELISA. The enhancing effect of zinc ion on the level of TPPP/p25 was independent of the expression level of the protein produced by doxycycline induction at different levels or inhibition of the protein synthesis by cycloheximide. Thus, we suggest that the zinc as a specific divalent cation could be involved in the fine-tuning of the physiological TPPP/p25 level counteracting both the enrichment and the lack of this protein leading to distinct central nervous system diseases.
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: lehotzky.attila@ttk.mta.hu.
authors.forename: Attila
authors.initials: A
authors.lastname: Lehotzky
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: olah.judit@ttk.mta.hu.
authors.forename: Judit
authors.initials: J
authors.lastname: Oláh
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: szunyogh.sandor@ttk.mta.hu.
authors.forename: Sándor
authors.initials: S
authors.lastname: Szunyogh
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: szaboadel90@gmail.com.
authors.forename: Adél
authors.initials: A
authors.lastname: Szabó
authors.affiliation: Department of Immunology and Biotechnology, Medical School, University of Pécs, Pécs, Hungary. Electronic address: timea.berki@aok.pte.hu.
authors.forename: Tímea
authors.initials: T
authors.lastname: Berki
authors.affiliation: Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, Budapest, Hungary. Electronic address: ovadi.judit@ttk.mta.hu.
authors.forename: Judit
authors.initials: J
authors.lastname: Ovádi
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D019281:Dimerization; D004797:Enzyme-Linked Immunosorbent Assay; D009419:Nerve Tissue Proteins / Q000737:chemistry* / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D011487:Protein Conformation; D059748:Proteolysis; D015032:Zinc / Q000378:metabolism / Q000502:physiology*
chemical_list: D009419:Nerve Tissue Proteins; C118136:TPPP protein, human; D046988:Proteasome Endopeptidase Complex; D015032:Zinc
keywords: Oligodendrocyte; Tubulin Polymerization Promoting Protein/p25; Zinc