Challenging Drug Target for Parkinson's Disease: Pathological Complex of the Chameleon TPPP/p25 and Alpha-synuclein Proteins
Document Type
Article
Publication Date
2017
Keywords
Tubulin Polymerization Promoting Protein/p25, α-Synuclein, Deletion mutants, Protein chameleon, Drug target, Bimolecular fluorescence complementation
Digital Object Identifier (DOI)
https://doi.org/10.1016/j.bbadis.2016.09.017
Abstract
The hallmarks of Parkinson's disease and other synucleinopathies, Tubulin Polymerization Promoting Protein (TPPP/p25) and α-synuclein (SYN) have two key features: they are disordered and co-enriched/co-localized in brain inclusions. These Neomorphic Moonlighting Proteins display both physiological and pathological functions due to their interactions with distinct partners. To achieve the selective targeting of the pathological TPPP/p25-SYN but not the physiological TPPP/p25-tubulin complex, their interfaces were identified as a specific innovative strategy for the development of anti-Parkinson drugs. Therefore, the interactions of TPPP/p25 with tubulin and SYN were characterized which suggested the involvements of the 178–187 aa and 147–156 aa segments in the complexation of TPPP/p25 with tubulin and SYN, respectively. However, various truncated and deletion mutants reduced but did not abolish the interactions except one mutant; in addition synthetized fragments corresponding to the potential binding segments of TPPP/p25 failed to interact with SYN. In fact, the studies of the multiple interactions at molecular and cellular levels revealed the high conformational plasticity, chameleon feature, of TPPP/p25 that ensures exceptional functional resilience; the lack of previously identified binding segments could be replaced by other segments. The experimental results are underlined by distinct bioinformatics tools. All these data revealed that although targeting chameleon proteins is a challenging task, nevertheless, the validation of a drug target can be achieved by identifying the interface of complexes of the partner proteins existing at the given pathological conditions.
Was this content written or created while at USF?
Yes
Citation / Publisher Attribution
Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease, v. 1863, issue 1, p. 310-323
Scholar Commons Citation
Szénási, Tibor; Oláh, Judit; Szabó, Adél; Szunyogh, Sándor; Láng, András; Perczel, András; Lehotzky, Attila; Uversky, Vladimir N.; and Ovádi, Judit, "Challenging Drug Target for Parkinson's Disease: Pathological Complex of the Chameleon TPPP/p25 and Alpha-synuclein Proteins" (2017). Molecular Medicine Faculty Publications. 304.
https://digitalcommons.usf.edu/mme_facpub/304
