Challenging drug target for Parkinson's disease: Pathological complex of the chameleon TPPP/p25 and alpha-synuclein proteins.
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.
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: szenasi.tibor@ttk.mta.hu.
Tibor
T
Szénási
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: olah.judit@ttk.mta.hu.
Judit
J
Oláh
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: szabo.adel@ttk.mta.hu.
Adél
A
Szabó
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: szunyogh.sandor@ttk.mta.hu.
Sándor
S
Szunyogh
MTA-ELTE, Protein Modelling Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest 1117, Hungary. Electronic address: langax@chem.elte.hu.
András
A
Láng
MTA-ELTE, Protein Modelling Research Group, Institute of Chemistry, Eötvös Loránd University, Budapest 1117, Hungary; Laboratory of Structural Chemistry and Biology, Institute of Chemistry, Eötvös Loránd University, Budapest 1117, Hungary. Electronic address: perczel@chem.elte.hu.
András
A
Perczel
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: lehotzky.attila@ttk.mta.hu.
Attila
A
Lehotzky
Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, 33612 Tampa, FL, USA; Laboratory of Structural Dynamics, Stability and Folding of Proteins, Institute of Cytology, Russian Academy of Sciences, St. Petersburg, Russia. Electronic address: vuversky@health.usf.edu.
Vladimir N
VN
Uversky
Institute of Enzymology, Research Center for Natural Sciences, Hungarian Academy of Sciences, Budapest 1117, Hungary. Electronic address: ovadi.judit@ttk.mta.hu.
Judit
J
Ovádi
D000595:Amino Acid Sequence; D006367:HeLa Cells; D006801:Humans; D058990:Molecular Targeted Therapy; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D010300:Parkinson Disease / Q000188:drug therapy / Q000378:metabolism*; D060066:Protein Interaction Maps; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D017384:Sequence Deletion; D014404:Tubulin / Q000378:metabolism; D051844:alpha-Synuclein / Q000378:metabolism*
D009419:Nerve Tissue Proteins; D011994:Recombinant Proteins; C118136:TPPP protein, human; D014404:Tubulin; D051844:alpha-Synuclein
Bimolecular fluorescence complementation; Deletion mutants; Drug target; Protein chameleon; Tubulin Polymerization Promoting Protein/p25; α-Synuclein