Modular Organization and Combinatorial Energetics of Proline–Tyrosine Nuclear Localization Signals

@article{citeulike:2859143, abstract = {Proline\&\#8211;tyrosine nuclear localization signals (PY-NLSs) are recognized and transported into the nucleus by human Karyopherin (Kap) \&\#946;2/Transportin and yeast Kap104p. Multipartite PY-NLSs are highly diverse in sequence and structure, share a common C-terminal R/H/KX2\&\#8211;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 Kap\&\#946;2\&\#8211;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.}, author = {S\&\#252;el, Katherine E. and Gu, Hongmei and Chook, Yuh M. }, citeulike-article-id = {2859143}, doi = {10.1371/journal.pbio.0060137}, journal = {PLoS Biology}, keywords = {nuclear\_import, sequence\_motif}, month = {June}, number = {6}, pages = {e137+}, posted-at = {2008-06-03 14:59:07}, priority = {2}, title = {Modular Organization and Combinatorial Energetics of Proline\&\#8211;Tyrosine Nuclear Localization Signals}, url = {http://dx.doi.org/10.1371/journal.pbio.0060137}, volume = {6}, year = {2008} }

TY - JOUR ID - citeulike:2859143 L3 - citeulike-article-id:2859143 TI - Modular Organization and Combinatorial Energetics of Proline–Tyrosine Nuclear Localization Signals JF - PLoS Biology VL - 6 IS - 6 SP - e137 N2 - 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/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 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. KW - nuclear_import KW - sequence_motif AU - Süel, Katherine AU - Gu, Hongmei AU - Chook, Yuh PY - 2008/06/01/ UR - http://dx.doi.org/10.1371/journal.pbio.0060137 ER -