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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) β2/Transportin and yeast Kap104p. Multipartite PY-NLSs are highly diverse in sequence and structure, share a common C-terminal R/H/KX(2–5)PY motif, and can be subdivided...

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Detalles Bibliográficos
Autores principales: Süel, Katherine E, Gu, Hongmei, Chook, Yuh Min
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2008
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2408616/
https://www.ncbi.nlm.nih.gov/pubmed/18532879
http://dx.doi.org/10.1371/journal.pbio.0060137
Descripción
Sumario:Proline–tyrosine nuclear localization signals (PY-NLSs) are recognized and transported into the nucleus by human Karyopherin (Kap) β2/Transportin and yeast Kap104p. Multipartite PY-NLSs are highly diverse in sequence and structure, share a common C-terminal R/H/KX(2–5)PY 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 Kapβ2–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.