Dual life of TPPP/p25 evolved in physiological and pathological conditions

Abstract

Neomorphic Moonlighting Proteins perform distinct functions at physiological and pathological conditions without alterations at 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 HDAC6. In normal brain TPPP/p25 is expressed in oligodendrocytes and plays a crucial role in the formation of projections in the course of differentiation requested for axon ensheathment. At pathological conditions TPPP/p25 interacts with alpha-synuclein, forms 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 alpha-synuclein were established in human brain inclusions characteristic for Parkinson's disease and other synucleinopathies. The binding segments on TPPP/p25 involved in the physiological and pathological interactions were identified and validated at molecular and cell levels using recombinant proteins and transfected HeLa and inducible CHO10 cells expressing TPPP/p25. Our finding that distinct motives are responsible for the neomorphic moonlighting feature of TPPP/p25 has powerful innovative impact in anti-Parkinson drug research. KEYWORDSTPPP/p25, tubulin, alpha-synuclein, moonlighting, acetylation, Parkinson's disease NEOMORPHIC MOONLIGHTING PROTEINSThe recognition that there are proteins with more than one function was recognized two decades ago and this characteristic was termed as moonlighting [1]. These proteins perform multiple, independent functions that are not coded at gene level, do not stem from genetic alterations (gene fusion or splice variants), their functions are manifested themselves at protein level. The functions of these moonlighting proteins can vary as a consequence of changes in cellular localization, cell type, and their oligomeric state, concentrations of substrates, cofactors or products [1]. In addition to these types of proteins, in which all functions are considered "normal", there are proteins displaying a second function that is not considered as a "normal" one [2]. These are Neomorphic Moonlighting Proteins, physiological function of which can be converted into a pathological one mostly due to their hetero-associations with "pathological" partners distinct from the physiological ones [2,3].The major part of the intracellular proteins has well-defined secondary and tertiary structures; however, a number of in silico and experimental data have been accumulated indicating that a part of proteins does not bear well-defined 3D structure [4][5][6]. These proteins denoted as intrinsically unstructured or disordered proteins, are rather common in living cells and fulfill essential physiological functions [4,5]. These functions are linked...

A high-content RNAi screen reveals multiple roles for long noncoding RNAs in cell division

“…This suggests that linc00899-dependent suppression of TPPP could be 5 used to fine-tune TPPP expression, and hence microtubule behaviour in a developmental stage-and tissue-specific manner. Intriguingly, altered TPPP protein levels have been observed in a number of neurodegenerative disorders including multiple sclerosis and Parkinson's disease 62, 63 .…”

Drosophila Ringmaker regulates microtubule stabilization and axonal extension during embryonic development

“…Additionally, Ringer loss might lead to depolymerization due to higher susceptibility to severing agents (McNally and Vale, 1993;Qiang et al, 2006). Perhaps there are Ringer concentration thresholds (Olah and Ovadi, 2014), posttranslational modifications (Kleinnijenhuis et al, 2008) or other factors (Takahashi et al, 1991;Tő kési et al, 2010) that decide in favor of a specific function.…”

Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins

“…TPPP/p25 modulates the dynamics and stability of the microtubule system, where it is primarily engaged in the development of projections of oligodendrocytes that are responsible for the ensheathment of axons [7,9,11]. A couple of specific binding domains in the disordered TPPP/p25 have been identified both sequentially and experimentally such as a zinc finger motif, consensus GTP binding domain, phosphorylation sites, and the functional consequences of these sites have been established ( [12] and references therein). The non-physiological expression levels of this IDP lead to…”