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Alpha-Synuclein with H2a-H2b dimer complex structure.
Structural highlights
FunctionH2B11_XENLA Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling.H2A1_XENLA Core component of nucleosome. Nucleosomes wrap and compact DNA into chromatin, limiting DNA accessibility to the cellular machineries which require DNA as a template. Histones thereby play a central role in transcription regulation, DNA repair, DNA replication and chromosomal stability. DNA accessibility is regulated via a complex set of post-translational modifications of histones, also called histone code, and nucleosome remodeling. Publication Abstract from PubMedalpha-Synuclein (alphaSyn) plays a critical role in the pathogenesis of 'Synucleinopathies'. Although increased nuclear alphaSyn localization induces neurotoxicity, its definitive physiological role remains elusive. Previous studies on nuclear alphaSyn are limited to its interactions with individual histones and dsDNA, leaving a significant gap in understanding its interactions with assembled histone H2a-H2b dimer and (H3-H4)(2) tetramer, as well as its role in chromatin regulation. Here, we demonstrate that alphaSyn binds specifically to both H2a-H2b and (H3-H4)(2) with high affinity. Truncation studies reveal that alphaSyn(1-103) region interacts with (H3-H4)(2), while the acidic (121-140) C-terminal end is crucial for H2a-H2b binding and contains a conserved DEF/YxP motif present in other dimer-binding histone chaperones. High-resolution structure of alphaSyn(121-140) with H2a-H2b complex reveals that alphaSyn adopts two binding modes (BM-1 and BM-2). Nonetheless, the alphaSyn C-terminal end in both modes overlap but runs in opposite orientations, specifically interacting with the H2a-L2 and H2b-L1 loop regions of the dimer and cap the H2a-R78 residue. Mutational analysis confirms that alphaSyn-Y136 and P138 residues, part of the DEF/YxP motif, together with H2a-R78, are critical for alphaSyn-(H2a-H2b) interaction. The chaperoning assay supports alphaSyn's function as a histone chaperone, suggesting the potential role of alphaSyn in the nucleosome assembly/disassembly process. Structural and functional insights into the nuclear role of Parkinson's disease-associated alpha-synuclein as a histone chaperone.,Jos S, Kambaru A, Prasad TK, Parthasarathi S, Kamariah N, Nath S, Padmanabhan B, Padavattan S Commun Biol. 2025 May 8;8(1):712. doi: 10.1038/s42003-025-08138-0. PMID:40341765[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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