Evidence supporting a critical contribution of intrinsically disordered regions to the biochemical behavior of full-length human HP1纬

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• 作者：Gabriel Velez ; Marisa Lin ; Trace Christensen…
• 关键词：HP1 ; HP1纬 ; CBX3 ; Molecular modeling ; Molecular dynamics ; Epigenetics ; Chromatin
• 刊名：Journal of Molecular Modeling
• 出版年：2016
• 出版时间：January 2016
• 年：2016
• 卷：22
• 期：1
• 全文大小：7,694 KB
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• 作者单位：Gabriel Velez (1) (2) (3) (4)
  Marisa Lin (1) (2) (3)
  Trace Christensen (1) (2) (3)
  William A. Faubion (1) (2) (3)
  Gwen Lomberk (1) (2) (3)
  Raul Urrutia (1) (2) (3)
  
  1. Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Department of Biochemistry and Molecular Biology, Mayo Clinic, 200 First Street SW, Guggenheim 10, Rochester, MN, 55905, USA
  2. Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Department of Biophysics, Mayo Clinic, Rochester, MN, USA
  3. Laboratory of Epigenetics and Chromatin Dynamics, Gastroenterology Research Unit, Department of Medicine, Mayo Clinic, Rochester, MN, USA
  4. Medical Scientist Training Program, University of Iowa, Iowa City, IA, USA
  
• 刊物类别：Chemistry and Materials Science
• 刊物主题：Chemistry
  Computer Applications in Chemistry
  Biomedicine
  Molecular Medicine
  Health Informatics and Administration
  Life Sciences
  Computer Application in Life Sciences
  
• 出版者：Springer Berlin / Heidelberg
• ISSN：0948-5023

文摘

HP1纬, a non-histone chromatin protein, has elicited significant attention because of its role in gene silencing, elongation, splicing, DNA repair, cell growth, differentiation, and many other cancer-associated processes, including therapy resistance. These characteristics make it an ideal target for developing small drugs for both mechanistic experimentation and potential therapies. While high-resolution structures of the two globular regions of HP1纬, the chromo- and chromoshadow domains, have been solved, little is currently known about the conformational behavior of the full-length protein. Consequently, in the current study, we use threading, homology-based molecular modeling, molecular mechanics calculations, and molecular dynamics simulations to develop models that allow us to infer properties of full-length HP1纬 at an atomic resolution level. HP1纬 appears as an elongated molecule in which three Intrinsically Disordered Regions (IDRs, 1, 2, and 3) endow this protein with dynamic flexibility, intermolecular recognition properties, and the ability to integrate signals from various intracellular pathways. Our modeling also suggests that the dynamic flexibility imparted to HP1纬 by the three IDRs is important for linking nucleosomes with PXVXL motif-containing proteins, in a chromatin environment. The importance of the IDRs in intermolecular recognition is illustrated by the building and study of both IDR2 HP1纬鈭抜mportin-伪 and IDR1 and IDR2 HP1纬鈭扗NA complexes. The ability of the three IDRs for integrating cell signals is demonstrated by combined linear motif analyses and molecular dynamics simulations showing that posttranslational modifications can generate a histone mimetic sequence within the IDR2 of HP1纬, which when bound by the chromodomain can lead to an autoinhibited state. Combined, these data underscore the importance of IDRs 1, 2, and 3 in defining the structural and dynamic properties of HP1纬, discoveries that have both mechanistic and potentially biomedical relevance. Keywords HP1 HP1纬 CBX3 Molecular modeling Molecular dynamics Epigenetics Chromatin