Protein disorder-to-order transition enhances the nucleosome-binding affinity of H1
Open Access
- 3 June 2020
- journal article
- research article
- Published by Oxford University Press (OUP) in Nucleic Acids Research
- Vol. 48 (10), 5318-5331
- https://doi.org/10.1093/nar/gkaa285
Abstract
Intrinsically disordered proteins are crucial elements of chromatin heterogenous organization. While disorder in the histone tails enables a large variation of inter-nucleosome arrangements, disorder within the chromatin-binding proteins facilitates promiscuous binding to a wide range of different molecular targets, consistent with structural heterogeneity. Among the partially disordered chromatin-binding proteins, the H1 linker histone influences a myriad of chromatin characteristics including compaction, nucleosome spacing, transcription regulation, and the recruitment of other chromatin regulating proteins. Although it is now established that the long C-terminal domain (CTD) of H1 remains disordered upon nucleosome binding and that such disorder favours chromatin fluidity, the structural behaviour and thereby the role/function of the N-terminal domain (NTD) within chromatin is yet unresolved. On the basis of microsecond-long parallel-tempering metadynamics and temperature-replica exchange atomistic molecular dynamics simulations of different H1 NTD subtypes, we demonstrate that the NTD is completely unstructured in solution but undergoes an important disorder-to-order transition upon nucleosome binding: it forms a helix that enhances its DNA binding ability. Further, we show that the helical propensity of the H1 NTD is subtype-dependent and correlates with the experimentally observed binding affinity of H1 subtypes, suggesting an important functional implication of this disorder-to-order transition.Funding Information
- European Research Council (803326)
- Red Española de Supercomputación (QCM-2018-3-0041, QCM-2018-2-0037)
- University of Cambridge Research Computing Service
- EPSRC (EP/P020259/1)
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