Karyopherin-? (Kap) proteins mediate the majority of protein transport between the nucleus and the cytoplasm. Of the 20 Kaps in human cells, 11 are import-Kaps or Importins, each recognizing a distinct set of protein cargos. This proposal describes structural, biochemical and biophysical analyses of nuclear import systems for core histones H2A/H2B and H3/H4. Here, we propose to understand how histones H2A/H2B are recognized by their primary human importer Importin-9 (Imp9) and by the homologous yeast Kap114. We will determine the mechanisms of how H2A/H2B is recognized by the Importins, how the GTPase Ran interacts with the Importin- H2A/H2B complex and how histone chaperones affect these interactions. We will also study how histones H3/H4 are recognized by their primary human importer, Importin-4 (Imp4). We will explain how histone chaperone Asf1 contributes to nuclear import of H3/H4 and how RanGTP regulates these multi-protein complexes.

Public Health Relevance

Transport of histones into the nucleus is an essential and fundamental cellular process that is immediately downstream of histone synthesis/processing in the cytoplasm and immediately upstream of nucleosome assembly in the nucleus. Steps in histone processing, nuclear import and deposition are likely tightly coordinated. It is therefore important to understand the molecular mechanisms of the individual steps of histone import beyond identification of the Importins and participating histone chaperones. 1

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM069909-15
Application #
9438545
Study Section
Nuclear and Cytoplasmic Structure/Function and Dynamics Study Section (NCSD)
Program Officer
Faupel-Badger, Jessica
Project Start
2004-02-01
Project End
2021-01-31
Budget Start
2018-02-01
Budget End
2019-01-31
Support Year
15
Fiscal Year
2018
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
Fung, Ho Yee Joyce; Fu, Szu-Chin; Chook, Yuh Min (2017) Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals. Elife 6:
Volpon, Laurent; Culjkovic-Kraljacic, Biljana; Osborne, Michael J et al. (2016) Importin 8 mediates m7G cap-sensitive nuclear import of the eukaryotic translation initiation factor eIF4E. Proc Natl Acad Sci U S A 113:5263-8
Soniat, Michael; Chook, Yuh Min (2016) Karyopherin-?2 Recognition of a PY-NLS Variant that Lacks the Proline-Tyrosine Motif. Structure 24:1802-1809
Soniat, Michael; Ca?atay, Tolga; Chook, Yuh Min (2016) Recognition Elements in the Histone H3 and H4 Tails for Seven Different Importins. J Biol Chem 291:21171-21183
Hing, Z A; Fung, H Y J; Ranganathan, P et al. (2016) Next-generation XPO1 inhibitor shows improved efficacy and in vivo tolerability in hematological malignancies. Leukemia 30:2364-2372
Fung, Ho Yee Joyce; Fu, Szu-Chin; Brautigam, Chad A et al. (2015) Structural determinants of nuclear export signal orientation in binding to exportin CRM1. Elife 4:
Haines, Jeffery D; Herbin, Olivier; de la Hera, Belén et al. (2015) Nuclear export inhibitors avert progression in preclinical models of inflammatory demyelination. Nat Neurosci 18:511-20
Xu, Darui; Marquis, Kara; Pei, Jimin et al. (2015) LocNES: a computational tool for locating classical NESs in CRM1 cargo proteins. Bioinformatics 31:1357-65
Soniat, Michael; Chook, Yuh Min (2015) Nuclear localization signals for four distinct karyopherin-? nuclear import systems. Biochem J 468:353-62
Fung, Ho Yee Joyce; Chook, Yuh Min (2014) Atomic basis of CRM1-cargo recognition, release and inhibition. Semin Cancer Biol 27:52-61

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