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S-nitrosylation of UCHL1 induces its structural instability and promotes ?-synuclein aggregation.

ABSTRACT: Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed which alters the catalytic activity and structural stability. We show here that nitrosylation induces structural instability and produces amorphous aggregate, which provides a nucleation to the native ?-synuclein for faster aggregation. Our findings provide a new link between UCHL1-nitrosylation and PD pathology.

SUBMITTER: Kumar R

PROVIDER: S-EPMC5353675 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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S-nitrosylation of UCHL1 induces its structural instability and promotes α-synuclein aggregation.

Kumar Roshan R Jangir Deepak K DK Verma Garima G Shekhar Shashi S Hanpude Pranita P Kumar Sanjay S Kumari Raniki R Singh Nirpendra N Sarovar Bhavesh Neel N Ranjan Jana Nihar N Kanti Maiti Tushar T

Scientific reports 20170316

Ubiquitin C-terminal Hydrolase-1 (UCHL1) is a deubiquitinating enzyme, which plays a key role in Parkinson's disease (PD). It is one of the most important proteins, which constitute Lewy body in PD patient. However, how this well folded highly soluble protein presents in this proteinaceous aggregate is still unclear. We report here that UCHL1 undergoes S-nitrosylation in vitro and rotenone induced PD mouse model. The preferential nitrosylation in the Cys 90, Cys 152 and Cys 220 has been observed ...[more]

PMID: 28300150

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Project description:Aggregation of ?-Synuclein (?S) protein to amyloid fibrils is a neuropathological hallmark of Parkinson's disease (PD). Growing evidence suggests that extracellular ?S aggregation plays a pivotal role in neurodegeneration found in PD in addition to the intracellular ?S aggregates in Lewy bodies (LB). Here, we identified and compared a diverse set of molecules capable of mitigating protein aggregation and exogenous toxicity of ?SA53T, a more aggregation-prone ?S mutant found in familial PD. For the first time, we investigated the ?S anti-amyloid activity of semi-synthetic flavonoid 2', 3', 4' trihydroxyflavone or 2-D08, which was compared with natural flavones myricetin and transilitin, as well as such structurally diverse polyphenols as honokiol and punicalagin. Additionally, two novel synthetic compounds with a dibenzyl imidazolidine scaffold, Compound 1 and Compound 2, were also investigated as they exhibited favorable binding with ?SA53T. All seven compounds inhibited ?SA53T aggregation as demonstrated by Thioflavin T fluorescence assays, with modified fibril morphology observed by transmission electron microscopy. Ion mobility-mass spectrometry (IM-MS) was used to monitor the structural conversion of native ?SA53T into amyloidogenic conformations and all seven compounds preserved the native unfolded conformations of ?SA53T following 48 h incubation. The presence of each test compound in a 1:2 molar ratio was also shown to inhibit the neurotoxicity of preincubated ?SA53T using phaeochromocytoma (PC12) cell viability assays. Among the seven tested compounds 2-D08, honokiol, and the synthetic Compound 2 demonstrated the highest inhibition of aggregation, coupled with neuroprotection from preincubated ?SA53T in vitro. Molecular docking predicted that all compounds bound near the lysine-rich region of the N-terminus of ?SA53T, where the flavonoids and honokiol predominantly interacted with Lys 23. Overall, these findings highlight that (i) restricted vicinal trihydroxylation in the flavone B-ring is more effective in stabilizing the native ?S conformations, thus blocking amyloidogenic aggregation, than dihydroxylation aggregation in both A and B-ring, and (ii) honokiol, punicalagin, and the synthetic imidazolidine Compound 2 also inhibit ?S amyloidogenic aggregation by stabilizing its native conformations. This diverse set of molecules acting on a singular pathological target with predicted binding to ?SA53T in the folding-prone N-terminal region may contribute toward novel drug-design for PD.

Dataset Information

S-nitrosylation of UCHL1 induces its structural instability and promotes ?-synuclein aggregation.

Publications

S-nitrosylation of UCHL1 induces its structural instability and promotes α-synuclein aggregation.

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