Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 284, Issue 30, Pages 20428-20439Publisher
AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC
DOI: 10.1074/jbc.M109.004242
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Funding
- National Natural Science Foundation of China [3047085, 90608007]
- Ministry of Science and Technology of China [2006AA02A310]
- National Institutes of Health [NS46616]
- NINDS [NS46616]
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Nuclear import of proteins with nuclear localization signals (NLSs) is mediated by shuttling carriers, the importins. Some cargoes display more than a single NLS, and among these are homeodomain proteins such as Arx, which is critical for development of multiple tissues. Arx has two functional NLSs. The present studies show that several pathways can import Arx via its NLS2, which is within its DNA binding homeodomain. Using an in vitro nuclear import assay, we show that import of Arx via NLS2 can be mediated by importin beta 1, importin 9, or importin 13, with binding being strongest to importin beta 1. All binding is sensitive to RanGTP. Experiments based on precise domain deletions indicate that NLS2 binds imp beta 1, imp9, and imp13 and includes both an importin binding subdomain and a regulatory subdomain with arginine residues being important for function. Moreover, Arx can be co-precipitated with these importins when NLS2 is present. Although nuclear import of Arx can be mediated by these three importin beta s, importin beta 1 seems to play the major role judging from in vivo small interfering RNA ablations and the in vitro import assay. This is the first evidence to show the role of importin beta 1 in nuclear import of paired-type homeodomain proteins. We propose a novel and possibly quite general mechanism for nuclear import of paired-type homeodomain proteins which is critical for development.
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