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Albany 2013: Book of Abstracts

category image Albany 2013
Conversation 18
June 11-15 2013
©Adenine Press (2012)

A Dynamic Model for the Linker Histone

Linker histones play an important role in the packing of chromatin. This family of proteins generally consists of a short, unstructured N-terminal domain, a central globular domain and a C-terminal domain (CTD). The CTD, which makes up roughly half of the protein, is intrinsically disordered in solution but adopts a specific fold upon interaction with DNA (Fang et al., 2012). While the globular domain structure is well characterized, the structure of the CTD remains unknown. Sequence alignment alone does not reveal any significant homologues for this region of the protein. Construction of a model thus requires additional information. For example, the atomic model for the rat histone H1d CTD, proposed over a decade ago, used novel bioinformatics tools and biochemical data (Bharath et al., 2002). New fluorescence resonance energy transfer (FRET) studies of the folding of the CTD in the presence of linear DNA, single nucleosomes and oligonucleosomal arrays (Caterino et al., 2011; Fang et al., 2012) have stimulated our interest in constructing a dynamic model of the protein. We have obtained preliminary information about the structure and dynamics of the linker histone CTD through ab initio folding simulations using the Rosetta modeling package (Rohl et al., 2004). By analyzing a large number of conformations sampled through a Monte Carlo procedure we get a clearer picture of the preferred states of the protein and its dynamics. Our results show that the CTD may frequently adopt a structure with 3-5 helices and helix-turn-helix motifs in specific regions. Some of the best scoring structures show high similarity with the HMG-box-containing proteins previously used as templates by Bharath et al. Further clustering analysis of our results hints of a preferred set of conformations for the C-terminal domain of the linker histone. Comparison of these models with distances measured by FRET may help account for the distinct structures of the CTD observed upon binding to different macromolecular partners.

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Helix propensities in the linker histone H5 CTD among 50,000 structures predicted by Rosetta

References

    Bharath, M.M., Chandra, N.R. and Rao, M.R. (2002) Prediction of an HMG-box fold in the C-terminal domain of histone H1: insights into its role in DNA condensation. Proteins, 49, 71-81.

    Caterino T.L., Fang H. and Hayes J.J. (2011) Nucleosome linker DNA contacts and induces specific folding of the intrinsically disordered H1 carboxyl-terminal domain. Mol Cell Biol, 31, 2341–2348

    Fang, H., Clark, D.J. and Hayes, J.J. (2012) DNA and nucleosomes direct distinct folding of a linker histone H1 C-terminal domain. Nucleic Acids Res, 40, 1475-1484.

    Rohl, C.A., Strauss, C.E.M., Misura, K.M.S. and Baker, D. (2004) Protein structure prediction using Rosetta. Methods in Enzymology: Numerical Computer Methods, 383, 66-93.


Stefjord Todolli
Wilma K. Olson

BioMaPS Institute for Quantitative Biology
Rutgers University
Piscataway, NJ 08854

Phone: (732) 445-4619
stefjord.todolli@rutgers.edu