Dual life of TPPP/p25 evolved in physiological and pathological conditions.
Neomorphic moonlighting proteins perform distinct functions under physiological and pathological conditions without alterations at the gene level. The disordered tubulin-polymerization-promoting protein (TPPP/p25), a prototype of neomorphic moonlighting proteins, modulates the dynamics and stability of the microtubule system via its bundling and tubulin acetylation-promoting activities. These physiological functions are mediated by its direct associations with tubulin/microtubules as well as tubulin deacetylases such as histone deacetylase (HDAC) 6. In a normal brain, TPPP/p25 is expressed in oligodendrocytes and plays a crucial role in the formation of projections in the course of differentiation required for axon ensheathment. Under pathological conditions, TPPP/p25 interacts with α-synuclein, an aberrant protein-protein interaction resulting in aggregation leading to the formation of inclusions as clinical symptoms. The co-enrichment and co-localization of TPPP/p25 and α-synuclein were established in human-brain inclusions characteristic of Parkinson's disease (PD) and other synucleinopathies. The binding segments on TPPP/p25 involved in the physiological and the pathological interactions were identified and validated at molecular and cellular levels using recombinant proteins and transfected HeLa and inducible Chinese-hamster ovary (CHO) 10 cells expressing TPPP/p25. Our finding that distinct motifs are responsible for the neomorphic moonlighting feature of TPPP/p25, has powerful innovative effects in anti-Parkinson's disease drug research.
*Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
Judit
J
Oláh
*Institute of Enzymology, Research Centre for Natural Sciences, Hungarian Academy of Sciences, H-1117 Budapest, Hungary.
Judit
J
Ovádi
D000818:Animals; D004194:Disease; D006801:Humans; D008024:Ligands; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D011485:Protein Binding
D008024:Ligands; D009419:Nerve Tissue Proteins; C118136:TPPP protein, human