TY - JOUR
T1 - Structural prerequisites for CRM1-dependent nuclear export signaling peptides
T2 - accessibility, adapting conformation, and the stability at the binding site
AU - Lee, Yoonji
AU - Pei, Jimin
AU - Baumhardt, Jordan M.
AU - Chook, Yuh Min
AU - Grishin, Nick V.
N1 - Funding Information:
This work is funded by the Cancer Prevention Research Institute of Texas (CPRIT) Grants RP170170 (N.V.G. and Y.M.C.) and RP180410 (Y.M.C.), the National Institutes of Health Grant (GM127390 to N.V.G.) and Welch Foundation Grants (I-1532 to Y.M.C and I-1505 to N.V.G). The authors acknowledge the Texas Advanced Computing Center (TACC; http://www.tacc.utexas.edu) at The University of Texas at Austin for providing HPC resources.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - Nuclear export signal (NES) motifs function as essential regulators of the subcellular location of proteins by interacting with the major nuclear exporter protein, CRM1. Prediction of NES is of great interest in many aspects of research including cancer, but currently available methods, which are mostly based on the sequence-based approaches, have been suffered from high false positive rates since the NES consensus patterns are quite commonly observed in protein sequences. Therefore, finding a feature that can distinguish real NES motifs from false positives is desired to improve the prediction power, but it is quite challenging when only using the sequence. Here, we provide a comprehensive table for the validated cargo proteins, containing the location of the NES consensus patterns with the disordered propensity plots, known protein domain information, and the predicted secondary structures. It could be useful for determining the most plausible NES region in the context of the whole protein sequence and suggests possibilities for some non-binders of the annotated regions. In addition, using the currently available crystal structures of CRM1 bound to various classes of NES peptides, we adopted, for the first time, the structure-based prediction of the NES motifs bound to the CRM1’s binding groove. Combining sequence-based and structure-based predictions, we suggest a novel and more straight-forward approach to identify CRM1-binding NES sequences by analysis of their structural prerequisites and energetic evaluation of the stability at the CRM1’s binding site.
AB - Nuclear export signal (NES) motifs function as essential regulators of the subcellular location of proteins by interacting with the major nuclear exporter protein, CRM1. Prediction of NES is of great interest in many aspects of research including cancer, but currently available methods, which are mostly based on the sequence-based approaches, have been suffered from high false positive rates since the NES consensus patterns are quite commonly observed in protein sequences. Therefore, finding a feature that can distinguish real NES motifs from false positives is desired to improve the prediction power, but it is quite challenging when only using the sequence. Here, we provide a comprehensive table for the validated cargo proteins, containing the location of the NES consensus patterns with the disordered propensity plots, known protein domain information, and the predicted secondary structures. It could be useful for determining the most plausible NES region in the context of the whole protein sequence and suggests possibilities for some non-binders of the annotated regions. In addition, using the currently available crystal structures of CRM1 bound to various classes of NES peptides, we adopted, for the first time, the structure-based prediction of the NES motifs bound to the CRM1’s binding groove. Combining sequence-based and structure-based predictions, we suggest a novel and more straight-forward approach to identify CRM1-binding NES sequences by analysis of their structural prerequisites and energetic evaluation of the stability at the CRM1’s binding site.
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U2 - 10.1038/s41598-019-43004-0
DO - 10.1038/s41598-019-43004-0
M3 - Article
C2 - 31036839
AN - SCOPUS:85065071630
SN - 2045-2322
VL - 9
JO - Scientific reports
JF - Scientific reports
IS - 1
M1 - 6627
ER -