@article {316,
	title = {Promiscuous Histone Mis-Assembly Is Actively Prevented by Chaperones.},
	journal = {J Am Chem Soc},
	volume = {138},
	year = {2016},
	month = {10/2016},
	pages = {13207-13218},
	abstract = {<p>Histone proteins are essential for the organization, expression, and inheritance of genetic material for eukaryotic cells. A centromere-specific H3 histone variant, centromere protein A (CENP-A), shares about 50\% amino acid sequence identity with H3. CENP-A is required for packaging the centromere and for the proper separation of chromosomes during mitosis. Despite their distinct biological functions, previously reported crystal structures of the CENP-A/H4 and H3/H4 dimers reveal a high degree of similarity. In this work, we characterize the structural dynamics of CENP-A/H4 and H3/H4 dimers based on a dual-resolution approach, using both microsecond-scale explicit-solvent all-atom and coarse-grained (CG) molecular dynamics (MD) simulations. Our data show that the H4 histone is significantly more rigid compared with the H3 histone and its variant CENP-A, hence, serving as a reinforcing structural element within the histone core. We report that the CENP-A/H4 dimer is significantly more dynamic than its canonical counterpart H3/H4, and our results provide a physical explanation for this flexibility. Further, we observe that the centromere-specific chaperone Holliday Junction Recognition Protein (HJURP) stabilizes the CENP-A/H4 dimer by forming a specific electrostatic interaction network. Finally, replacing CENP-A S68 with E68 disrupts the binding interface between CENP-A and HJURP in all-atom MD simulation, and consistently, in vivo experiments demonstrate that replacing CENP-A S68 with E68 disrupts CENP-A{\textquoteright}s localization to the centromere. Based on all our results, we propose that, during the CENP-A/H4 deposition process, the chaperone HJURP protects various substructures of the dimer, serving both as a folding and binding chaperone.</p>
},
	keywords = {Centromere Protein A, DNA-Binding Proteins, HeLa Cells, Histones, Humans, Molecular Dynamics Simulation, Protein Folding, Protein Multimerization, Protein Structure, Quaternary, Substrate Specificity},
	doi = {10.1021/jacs.6b05355},
	author = {Zhao*, Haiqing and Winogradoff*, David and Bui, Minh and Dalal, Yamini and Papoian, Garegin A}
}
