CENP-A Nucleosome is a Sensitive Allosteric Scaffold for DNA and Chromatin Factors |
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| Affiliation: | 1. Izmir Biomedicine and Genome Center, Dokuz Eylül University Health Campus, Balçova, Izmir 35330, Turkey;2. Izmir Biomedicine and Genome Institute, Dokuz Eylül University Health Campus, Balçova, Izmir 35330, Turkey;3. Université Grenoble Alpes, CNRS UMR 5309, INSERM U1209, Institute for Advanced Biosciences (IAB), Site Santé – Allée des Alpes, 38700 La Tronche, France;1. Department of Pharmacology, Vanderbilt University, Nashville, TN 37232, USA;2. The Center for Structural Biology, Vanderbilt University, Nashville, TN 37232, USA;3. Department of Biophysics, Medical College of Wisconsin, Milwaukee, WI 53226, USA;4. The Biophysics Collaborative Access Team (BioCAT), Department of Biological Chemical and Physical Sciences, Illinois Institute of Technology, Chicago, IL 60616, USA;5. University of California Los Angeles, Los Angeles, CA 90095, USA;6. Department of Biochemistry and the Vanderbilt Institute of Chemical Biology, Vanderbilt University, Nashville, TN 37232, USA;1. Center for Theoretical Biological Physics, Rice University, Houston, TX, USA;2. ICTP South American Institute for Fundamental Research, Instituto de Física Teórica, UNESP – 01140-070, São Paulo, SP, Brazil;3. Instituto de Biociências, Letras e Ciências Exatas, UNESP - Univ. Estadual Paulista, Departamento de Física, São José do Rio Preto, SP, Brazil;4. Chemical Engineering Department, Military Institute of Engineering, Rio de Janeiro, RJ, Brazil;1. Department of Molecular, Cellular, and Developmental Biology, University of Colorado Boulder, Boulder, CO 80303, United States;2. Department of Biochemistry, University of Colorado Boulder, Boulder, CO 80309, United States;3. Howard Hughes Medical Institute, Chevy Chase, MD 20815, United States;1. Department of Chemistry, New York University, 1021 Silver, 100 Washington Square East, New York, NY, 10003, USA;2. Perelman School of Medicine, Department of Physiology, University of Pennsylvania, Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA;3. Perelman School of Medicine, Department of Cell and Developmental Biology, University of Pennsylvania, Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104, USA;4. Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), 08003 Barcelona, Spain;5. Universitat Pompeu Fabra (UPF), Dr Aiguader 88, 08003 Barcelona, Spain;6. Institució Catalana de Recerca i Estudis Avançats (ICREA), Pg. Lluís Companys 23, 08010 Barcelona, Spain;7. Bioland Laboratory, Guangzhou Regenerative Medicine and Health Guangdong Laboratory, Guangzhou 510005, China;8. CAS Key Laboratory of Regenerative Biology, Guangdong Provincial Key Laboratory of Stem Cell and Regenerative Medicine, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou 510530, China;9. New York University-East China Normal University Center for Computational Chemistry at New York University Shanghai, Room 340, Geography Building, 3663 North Zhongshan Road, Shanghai, 200062, China;10. Courant Institute of Mathematical Sciences, New York University, 251 Mercer St, New York, NY, 10012, USA;1. Department of Chemistry and the Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL 60616, United States;2. Department of Physics and the Center for Molecular Study of Condensed Soft Matter, Illinois Institute of Technology, Chicago, IL 60616, United States;1. Biophysics Program, Institute for Physical Science and Technology, University of Maryland, College Park, MD 20742, United States;2. Laboratory of Receptor Biology and Gene Expression, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, United States;3. Department of Chemistry and Biochemistry, University of Maryland, College Park, MD 20742, United States |
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| Abstract: | Centromeric loci of chromosomes are defined by nucleosomes containing the histone H3 variant CENP-A, which bind their DNA termini more permissively than their canonical counterpart, a feature that is critical for the mitotic fidelity. A recent cryo-EM study demonstrated that the DNA termini of CENP-A nucleosomes, reconstituted with the Widom 601 DNA sequence, are asymmetrically flexible, meaning one terminus is more clearly resolved than the other. However, an earlier work claimed that both ends could be resolved in the presence of two stabilizing single chain variable fragment (scFv) antibodies per nucleosome, and thus are likely permanently bound to the histone octamer. This suggests that the binding of scFv antibodies to the histone octamer surface would be associated with CENP-A nucleosome conformational changes, including stable binding of the DNA termini. Here, we present computational evidence that allows to explain at atomistic level the structural rearrangements of CENP-A nucleosomes resulting from the antibody binding. The antibodies, while they only bind the octamer façades, are capable of altering the dynamics of the nucleosomal core, and indirectly also the surrounding DNA. This effect has more drastic implications for the structure and the dynamics of the CENP-A nucleosome in comparison to its canonical counterpart. Furthermore, we find evidence that the antibodies bind the left and the right octamer façades at different affinities, another manifestation of the DNA sequence. We speculate that the cells could use induction of similar allosteric effects to control centromere function. |
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| Keywords: | CENP-A nucleosome allostery molecular dynamics |
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