4.8 Article

Moderate Binding between Two SARS-CoV-2 Protein Segments and α-Synuclein Alters Its Toxic Oligomerization Propensity Differently

Journal

JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 13, Issue 45, Pages 10642-10648

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.2c02278

Keywords

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Funding

  1. Research Grant Council of Hong Kong
  2. [16102921]

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This study demonstrates the potential interactions between SARS-CoV-2 protein segments and neuronal proteins, suggesting a potential risk of post-infection neurodegeneration. The receptor-binding domain of the spike protein can inhibit the fibrillization of neuronal proteins, while a segment of the envelope protein can accelerate the formation of oligomers. These findings provide important molecular insights into the neurological effects of SARS-CoV-2 infection and its association with Parkinson's disease.
The neurological symptoms of long COVID and viral neuroinvasion have raised concerns about the potential interactions between SARS-CoV-2 protein segments and neuronal proteins, which might confer a risk of post-infection neurodegeneration, but the underlying mechanisms remain unclear. Here, we reported that the receptor-binding domain (RBD) of the spike protein and the nine-residue segment (SK9) of the envelope protein could bind to alpha- synuclein (alpha Syn) with Kd values of 503 +/- 24 nM and 12.7 +/- 1.6 mu M, respectively. RBD could inhibit alpha Syn fibrillization by blocking the non-amyloid-beta component region and mediating its antiparallel beta-sheet structural conversions. Omicron-RBD (BA.5) was shown to have a slightly stronger affinity for alpha Syn (Kd = 235 +/- 10 nM), which implies similar effects, whereas SK9 may bind to the C-terminus which accelerates the formation of parallel beta-sheet-containing oligomers and abruptly increases the rate of membrane disruption by 213%. Our results provide plausible molecular insights into the impact of SARS-CoV-2 post-infection and the oligomerization propensity of alpha Syn that is associated with Parkinson's disease.

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