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Modular organization and combinatorial energetics of proline-tyrosine nuclear localization signals.

Proline-tyrosine nuclear localization signals (PY-NLSs) are recognized and transported into the nucleus by human Karyopherin (Kap) beta2/Transportin and yeast Kap104p. Multipartite PY-NLSs are highly diverse in sequence and structure, share a common C-terminal R/H/KX2-5PY motif, and can be subdivided into hydrophobic and basic subclasses based on loose N-terminal sequence motifs. PY-NLS variability is consistent with weak consensus motifs, but such diversity potentially renders comprehensive genome-scale searches intractable. Here, we use yeast Kap104p as a model system to understand the energetic organization of this NLS. First, we show that Kap104p substrates contain PY-NLSs, demonstrating their generality across eukaryotes. Previously reported Kapbeta2-NLS structures explain Kap104p specificity for the basic PY-NLS. More importantly, thermodynamic analyses revealed physical properties that govern PY-NLS binding affinity: (1) PY-NLSs contain three energetically significant linear epitopes, (2) each epitope accommodates substantial sequence diversity, within defined limits, (3) the epitopes are energetically quasi-independent, and (4) a given linear epitope can contribute differently to total binding energy in different PY-NLSs, amplifying signal diversity through combinatorial mixing of energetically weak and strong motifs. The modular organization of the PY-NLS coupled with its combinatorial energetics lays a path to decode this diverse and evolvable signal for future comprehensive genome-scale identification of nuclear import substrates.

Pubmed ID: 18532879


  • Süel KE
  • Gu H
  • Chook YM


PLoS biology

Publication Data

June 3, 2008

Associated Grants

  • Agency: NIGMS NIH HHS, Id: 5-T32-GM008297
  • Agency: NIGMS NIH HHS, Id: R01-GM069909

Mesh Terms

  • Active Transport, Cell Nucleus
  • Binding Sites
  • Humans
  • Karyopherins
  • Nuclear Localization Signals
  • Proline
  • Saccharomyces cerevisiae Proteins
  • Thermodynamics
  • Tyrosine
  • beta Karyopherins