8XWD

Croy-EM structure of alpha synuclein fibril with EGCG

Summary for 8XWD

• Entry DOI: 10.2210/pdb8xwd/pdb
• EMDB information: 38733
• Descriptor: Alpha-synuclein, (2R,3R)-5,7-dihydroxy-2-(3,4,5-trihydroxyphenyl)-3,4-dihydro-2H-chromen-3-yl 3,4,5-trihydroxybenzoate (2 entities in total)
• Functional Keywords: protein fibril, amyloid
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 6
• Total formula weight: 89606.88

Authors

Li, X.,Liu, C. (deposition date: 2024-01-16, release date: 2025-02-26, Last modification date: 2025-04-30)

Primary citation

Li, X.,Bi, L.,Zhang, S.,Xu, Q.,Xia, W.,Tao, Y.,Wu, S.,Li, Y.,Le, W.,Kang, W.,Li, D.,Sun, B.,Liu, C.
Single-Molecule Insight Into alpha-Synuclein Fibril Structure and Mechanics Modulated by Chemical Compounds.
Adv Sci, 12:e2416721-e2416721, 2025

PubMed Abstract: α-Syn fibrils, a key pathological hallmark of Parkinson's disease, is closely associated with disease initiation and progression. Several small molecules are found to bind or dissolve α-syn fibrils, offering potential therapeutic applications. Here, an innovative optical tweezers-based, fluorescence-combined approach is developed to probe the mechanical characteristics of α-syn fibrils at the single-molecule level. When subjected to axial stretching, local deformation within α-syn fibrils appeared at forces above 50 pN. These structural alternations occurred stepwise and are irreversible, suggesting unfolding of individual α-syn molecules or subdomains. Additionally, α-syn fibrils exhibits high heterogeneity in lateral disruption, with rupture force ranging from 50 to 500 pN. The impact of different compounds on the structure and mechanical features of α-syn fibrils is further examined. Notably, epigallocatechin gallate (EGCG) generally attenuates the rupture force of fibrils by wedging into the N-terminal polar groove and induces fibril dissociation. Conversely, copper chlorophyllin A (CCA) attaches to four different sites wrapping around the fibril core, reinforcing the stability of the fibril against rupture forces. The work offers an effective method for characterizing single-fibril properties and bridges compound-induced structural alternations with mechanical response. These insights are valuable for understanding amyloid fibril mechanics and their regulation by small molecules.

PubMed: 39951335
DOI: 10.1002/advs.202416721

Experimental method

ELECTRON MICROSCOPY (3.1 Å)