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Crystal structure of the Capsaspora owczarzaki macroH2A macrodomain in complex with ADP-ribose
Structural highlights
FunctionH2AY_CAPO3 Variant histone H2A which replaces conventional H2A in a subset of nucleosomes where it represses transcription. 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.[UniProtKB:O93327] Specifically binds poly-ADP-ribose and plays a key role in NAD(+) metabolism (PubMed:34887560). Able to bind to the ends of poly-ADP-ribose chains created by PARP1 and cap them (PubMed:34887560). This prevents PARP1 from further addition of ADP-ribose and thus limits the consumption of nuclear NAD(+), allowing the cell to maintain proper NAD(+) levels in both the nucleus and the mitochondria to promote proper mitochondrial respiration (PubMed:34887560).[1] Publication Abstract from PubMedNAD metabolism is essential for all forms of life. Compartmental regulation of NAD(+) consumption, especially between the nucleus and the mitochondria, is required for energy homeostasis. However, how compartmental regulation evolved remains unclear. In the present study, we investigated the evolution of the macrodomain-containing histone variant macroH2A1.1, an integral chromatin component that limits nuclear NAD(+) consumption by inhibiting poly(ADP-ribose) polymerase 1 in vertebrate cells. We found that macroH2A originated in premetazoan protists. The crystal structure of the macroH2A macrodomain from the protist Capsaspora owczarzaki allowed us to identify highly conserved principles of ligand binding and pinpoint key residue substitutions, selected for during the evolution of the vertebrate stem lineage. Metabolic characterization of the Capsaspora lifecycle suggested that the metabolic function of macroH2A was associated with nonproliferative stages. Taken together, we provide insight into the evolution of a chromatin element involved in compartmental NAD regulation, relevant for understanding its metabolism and potential therapeutic applications. Evolution of a histone variant involved in compartmental regulation of NAD metabolism.,Guberovic I, Hurtado-Bages S, Rivera-Casas C, Knobloch G, Malinverni R, Valero V, Leger MM, Garcia J, Basquin J, Gomez de Cedron M, Frigole-Vivas M, Cheema MS, Perez A, Ausio J, Ramirez de Molina A, Salvatella X, Ruiz-Trillo I, Eirin-Lopez JM, Ladurner AG, Buschbeck M Nat Struct Mol Biol. 2021 Dec;28(12):1009-1019. doi: 10.1038/s41594-021-00692-5. , Epub 2021 Dec 9. PMID:34887560[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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