Biophysical characterization of α-synuclein and its controversial structure

Alderson, T. Reid; Markley, John L.

doi:10.4161/idp.26255

Cited by 62 publications

(51 citation statements)

References 141 publications

(350 reference statements)

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“…Future work has to resolve these discrepancies and elucidate whether NTA regulates physiological dimer formation or pathological aggregation of α-synuclein. For a recent review on this topic see Alderson and Markley (2013).…”

Section: Mammalsmentioning

confidence: 99%

The biological functions of Naa10 — From amino-terminal acetylation to human disease

Dörfel

Lyon

2015

Gene

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N-terminal acetylation (NTA) is one of the most abundant protein modifications known, and the N-terminal acetyltransferase (NAT) machinery is conserved throughout all Eukarya. Over the past 50 years, the function of NTA has begun to be slowly elucidated, and this includes the modulation of protein–protein interaction, protein-stability, protein function, and protein targeting to specific cellular compartments. Many of these functions have been studied in the context of Naa10/NatA; however, we are only starting to really understand the full complexity of this picture. Roughly, about 40% of all human proteins are substrates of Naa10 and the impact of this modification has only been studied for a few of them. Besides acting as a NAT in the NatA complex, recently other functions have been linked to Naa10, including post-translational NTA, lysine acetylation, and NAT/KAT-independent functions. Also, recent publications have linked mutations in Naa10 to various diseases, emphasizing the importance of Naa10 research in humans. The recent design and synthesis of the first bisubstrate inhibitors that potently and selectively inhibit the NatA/Naa10 complex, monomeric Naa10, and hNaa50 further increases the toolset to analyze Naa10 function.

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Section: Mammalsmentioning

confidence: 99%

The biological functions of Naa10 — From amino-terminal acetylation to human disease

Dörfel

Lyon

2015

Gene

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“…Although the intrinsically disordered SYN is predominantly unfolded at physiological conditions, in response to changes in its environment it is capable of adopting structurally unrelated conformations ranging from intrinsically disordered form to various partially folded conformations with different contents of secondary structural elements induced by low pH, high temperature, organic solvents, membranes, agrochemicals, or metal ions [19,20]. The structural properties of SYN have been extensively characterized under a variety of conditions [21][22][23][24][25][26][27][28][29]. Despite the fact that the unstructured C-terminal segment (45 aa) is involved in the modulation of SYN aggregation at extreme in vitro conditions, yet a terminal 30-residue-long peptide was found to be ineffective as a competitor in aggregation processes, indicating its chameleon nature [19].…”

Section: U N C O R R E C T E D P R O O Fmentioning

confidence: 99%

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

Szénási¹,

Oláh²,

Szabó³

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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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.

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“…Although its exact function remains to be defined, it is proposed to participate in synaptic vesicle release and trafficking, fatty acid binding, and regulation of enzymes, neurotransmitters and vesicles2. α-syn is the principal component of the Lewy bodies found in some neurological diseases termed synucleinopathies, such as Parkinson’s disease (PD), multiple system atrophy (MSA), dementia with Lewy bodies (DLB), neurodegeneration with brain iron accumulation (NBIA) and pure autonomic failure (PAF)3.…”

mentioning

confidence: 99%

The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

Sot

Rubio-Muñoz

Leal-Quintero

et al. 2017

Sci Rep

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The eukaryotic chaperonin CCT (chaperonin containing TCP-1) uses cavities built into its double-ring structure to encapsulate and to assist folding of a large subset of proteins. CCT can inhibit amyloid fibre assembly and toxicity of the polyQ extended mutant of huntingtin, the protein responsible for Huntington’s disease. This raises the possibility that CCT modulates other amyloidopathies, a still-unaddressed question. We show here that CCT inhibits amyloid fibre assembly of α-synuclein A53T, one of the mutants responsible for Parkinson’s disease. We evaluated fibrillation blockade in α-synuclein A53T deletion mutants and CCT interactions of full-length A53T in distinct oligomeric states to define an inhibition mechanism specific for α-synuclein. CCT interferes with fibre assembly by interaction of its CCTζ and CCTγ subunits with the A53T central hydrophobic region (NAC). This interaction is specific to NAC conformation, as it is produced once soluble α-synuclein A53T oligomers form and blocks the reaction before fibres begin to grow. Finally, we show that this association inhibits α-synuclein A53T oligomer toxicity in neuroblastoma cells. In summary, our results and those for huntingtin suggest that CCT is a general modulator of amyloidogenesis via a specific mechanism.

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Biophysical characterization of α-synuclein and its controversial structure

Cited by 62 publications

References 141 publications

The biological functions of Naa10 — From amino-terminal acetylation to human disease

The biological functions of Naa10 — From amino-terminal acetylation to human disease

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

The chaperonin CCT inhibits assembly of α-synuclein amyloid fibrils by a specific, conformation-dependent interaction

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