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Molecular and Cellular Biology, April 2001, p. 2779-2789, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2779-2789.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dimerization of Sterol Regulatory Element-Binding Protein 2 via the Helix-Loop-Helix-Leucine Zipper Domain Is a Prerequisite for Its Nuclear Localization Mediated by Importin beta

Emi Nagoshi1 and Yoshihiro Yoneda1,2,*

Department of Cell Biology and Neuroscience, Graduate School of Medicine,1 and Institute for Molecular and Cellular Biology,2 Osaka University, Suita, Osaka 565-0871, Japan

Received 7 August 2000/Returned for modification 11 September 2000/Accepted 21 January 2001

The sterol regulatory element-binding protein 2 (SREBP-2), a transcription factor of the basic helix-loop-helix-leucine zipper (bHLH-Zip) family, is synthesized in the form of a membrane-attached precursor molecule. When cells are deprived of sterols, a two-step proteolytic processing releases the transcriptionally active N-terminal segment of SREBP-2, thereby allowing it to enter the nucleus. In previous studies, we showed that the nuclear import of SREBP-2 occurs via the direct interaction of importin beta  with the HLH-Zip domain. In this study, in order to more completely understand the intracellular dynamics of SREBP-2, we focused on the manner by which importin beta  recognizes SREBP-2 at the initial step of the import. It was found that the active form of SREBP-2 exists as a stable dimer in solution and that the substitution of leucine residues for alanine in the leucine zipper motif disrupted the dimerization. It was also demonstrated that this mutant protein did not enter the nucleus either in vivo or in vitro. Solution binding assays, which involved the chemical cross-linking of wild-type or mutated SREBP-2 with importin beta , revealed that the import-active complex appeared to be composed of a dimeric form of SREBP-2 and importin beta . In addition, the SREBP-2 binding domain of importin beta  corresponded to an overlapping but not identical region for importin alpha  binding, which may explain how importin beta  is able to recognize the dimeric HLH-Zip directly. These results indicate that dimerization is a prerequisite process for the nuclear import of SREBP-2 mediated by importin beta .

* Corresponding author. Mailing address: Department of Cell Biology and Neuroscience, Graduate School of Medicine, Osaka University, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan. Phone: 81-6-6879-3210. Fax: 81-6-6879-3219. E-mail: yyoneda{at}anat3.med.osaka-u.ac.jp.

Molecular and Cellular Biology, April 2001, p. 2779-2789, Vol. 21, No. 8
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.8.2779-2789.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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