Targeting the interface of the pathological complex of α-synuclein and TPPP/p25
| Autor: | Tibor Szénási, Adél Szabó, Judit Oláh, Sándor Szunyogh, Judit Ovádi |
|---|---|
| Rok vydání: | 2015 |
| Předmět: |
Stereochemistry
Parkinson's disease animal diseases Peptide Biology Intrinsically disordered proteins law.invention Affinity chromatography law Neomorphic moonlighting function heterocyclic compounds Molecular Biology α-Synuclein chemistry.chemical_classification Synucleinopathies TPPP/p25 Microscale thermophoresis Wild type Molecular biology Molten globule nervous system diseases Binding motives nervous system chemistry health occupations Recombinant DNA Molecular Medicine |
| Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. 1852:2653-2661 |
| ISSN: | 0925-4439 |
| DOI: | 10.1016/j.bbadis.2015.09.012 |
| Popis: | The pathological interaction of intrinsically disordered proteins, such as α-synuclein (SYN) and Tubulin Polymerization Promoting Protein (TPPP/p25), is often associated with neurodegenerative disorders. These hallmark proteins are co-enriched and co-localized in brain inclusions of Parkinson's disease and other synucleinopathies; yet, their successful targeting does not provide adequate effect due to their multiple functions. Here we characterized the interactions of the human recombinant wild type SYN, its truncated forms (SYN(1-120), SYN(95-140)), a synthetized peptide (SYN(126-140)) and a proteolytic fragment (SYN(103-140)) with TPPP/p25 to identify the SYN segment involved in the interaction. The binding of SYN(103-140) to TPPP/p25 detected by ELISA suggested the involvement of a segment within the C-terminal of SYN. The studies performed with ELISA, Microscale Thermophoresis and affinity chromatography proved that SYN(95-140) and SYN(126-140) - in contrast to SYN(1-120) - displayed significant binding to TPPP/p25. Fluorescence assay with ANS, a molten globule indicator, showed that SYN, but not SYN(1-120) abolished the zinc-induced local folding of both the full length as well as the N- and C-terminal-free (core) TPPP/p25; SYN(95-140) and SYN(126-140) were effective as well. The aggregation-prone properties of the SYN species with full length or core TPPP/p25 visualized by immunofluorescent microscopy demonstrated that SYN(95-140) and SYN(126-140), but not SYN(1-120), induced co-enrichment and massive intracellular aggregation after their premixing and uptake from the medium. These data with their innovative impact could contribute to the development of anti-Parkinson drugs with unique specificity by targeting the interface of the pathological TPPP/p25-SYN complex. |
| Databáze: | OpenAIRE |
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