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Originally published In Press as doi:10.1074/jbc.M008522200 on October 18, 2000

J. Biol. Chem., Vol. 276, Issue 2, 1317-1325, January 12, 2001
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Dissection of a Nuclear Localization Signal*

Mary R. Hodel, Anita H. Corbett, and Alec E. HodelDagger

From the Department of Biochemistry, Emory University School of Medicine, Atlanta, Georgia 30322

The regulated process of protein import into the nucleus of a eukaryotic cell is mediated by specific nuclear localization signals (NLSs) that are recognized by protein import receptors. This study seeks to decipher the energetic details of NLS recognition by the receptor importin alpha  through quantitative analysis of variant NLSs. The relative importance of each residue in two monopartite NLS sequences was determined using an alanine scanning approach. These measurements yield an energetic definition of a monopartite NLS sequence where a required lysine residue is followed by two other basic residues in the sequence K(K/R)X(K/R). In addition, the energetic contributions of the second basic cluster in a bipartite NLS (~3 kcal/mol) as well as the energy of inhibition of the importin alpha  importin beta -binding domain (~3 kcal/mol) were also measured. These data allow the generation of an energetic scale of nuclear localization sequences based on a peptide's affinity for the importin alpha -importin beta  complex. On this scale, a functional NLS has a binding constant of ~10 nM, whereas a nonfunctional NLS has a 100-fold weaker affinity of 1 µM. Further correlation between the current in vitro data and in vivo function will provide the foundation for a comprehensive quantitative model of protein import.

* This work was supported by National Institutes of Health Grant GM-58728, a collaborative grant from the Human Frontiers in Science program (to A. H. C.), and National Science Foundation Grant MCB-9874548 (to A. E. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Dagger To whom correspondence should be addressed: Dept. of Biochemistry, Emory University School of Medicine, 1510 Clifton Rd., Rm. G234, Atlanta, GA 30322. Tel.: 404-727-8764; Fax: 404-727-3746; E-mail: ahodel@emory.edu.

Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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