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The roles of multiple importins for nuclear import of murine aristaless-related homeobox protein
Wenbo Lin1, Wenduo Ye1, Lanlan Cai1, Xinyi Meng1, Guifen Ke1, Caoxin Huang1, Zi Peng1, Yinhua Yu2, Jeffrey A. Golden3, Alan M. Tartakoff4, and Tao Tao15
From the 1 Xiamen University, China; , 2 University of Houston, China; , 3 University of Pennsylvania, China; , 4 Case Western Reserve University, China
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 β1, importin 9 or importin 13, with binding being strongest to importin β1. All binding is sensitive to RanGTP. Experiments based on precise domain deletions indicate that NLS2 binds impβ1, 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 βs, importin β1 seems to play the major role, judging from in vivo siRNA ablations and the in vitro import assay. This is the first evidence to show the role of importin β1 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 are critical for development.
