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J. Biol. Chem., Vol. 282, Issue 46, 33743-33751, November 16, 2007

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The High Mobility Group Box Transcription Factor Nhp6Ap Enters the Nucleus by a Calmodulin-dependent, Ran-independent Pathway^*

John A. Hanover, Dona C. Love, Nikki DeAngelis, Meghan E. O'Kane, Raquel Lima-Miranda, Timothy Schulz, Yi-Meng Yen, Reid C. Johnson, and William A. Prinz¹

From the Laboratory of Cell Biochemistry and Biology, NIDDK, National Institutes of Health, Bethesda, Maryland 20892-0851 and the Department of Biological Chemistry, UCLA Medical School, Los Angeles, California 90095-1737

A gradient of Ran·GTP typically regulates traffic through the nuclear pore by modulating association of receptors with cargo. However, here we demonstrate that the yeast high mobility group box transcription factor Nhp6Ap enters the nucleus via a novel nuclear localization signal recognized by calcium calmodulin in a process that does not require Ran. Calmodulin is strictly required for the nondiffusional nuclear entry of Nhp6Ap. Calmodulin and DNA exhibit mutually exclusive binding to NHP6A, indicating that the directionality of Nhp6Ap nuclear accumulation may be driven by DNA-dependent dissociation of calmodulin. Our findings demonstrate that calmodulin can serve as a molecular switch triggering nuclear entry with subsequent dissociation of calmodulin binding upon interaction of cargo with chromatin. This pathway appears to be evolutionarily conserved; mammalian high mobility group box transcription factors often have two nuclear localization signals: one a classical Ran-dependent signal and a second that binds calmodulin. The finding that Nhp6Ap nuclear entry requires calmodulin but not Ran indicates that Nhp6Ap is a good model for studying this poorly understood but evolutionarily conserved calmodulin-dependent nuclear import pathway.

Received for publication, July 17, 2007 , and in revised form, September 5, 2007.

^* This work was supported by the intramural research program of the NIDDK, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: 8 Center Dr. MSC 0851, NIDDK, National Institutes of Health, Bethesda, MD 20892-0851. Fax: 301-496-9431; E-mail: wprinz{at}helix.nih.gov.

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