Three-dimensional context rather than NLS amino acid sequence determines importin α subtype specificity for RCC1.

Authors

Rajeshwer S. Sankhala, Thomas Jefferson UniversityFollow
Ravi K. Lokareddy, Thomas Jefferson UniversityFollow
Salma Begum, Thomas Jefferson University
Ruth A. Pumroy, Thomas Jefferson University; University of UtahFollow
Richard E. Gillilan, Cornell University
Gino Cingolani, Thomas Jefferson UniversityFollow

Document Type

Article

Publication Date

12-1-2017

Comments

This article has been peer reviewed. It is the author’s final published version in Nature Communications

Volume 8, Issue 1, December 2017, Article number 979.

The published version is available at DOI: 10.1038/s41467-017-01057-7. Copyright © Sankhala et al.

Abstract

Active nuclear import of Ran exchange factor RCC1 is mediated by importin α3. This pathway is essential to generate a gradient of RanGTP on chromatin that directs nucleocytoplasmic transport, mitotic spindle assembly and nuclear envelope formation. Here we identify the mechanisms of importin α3 selectivity for RCC1. We find this isoform binds RCC1 with one order of magnitude higher affinity than the generic importin α1, although the two isoforms share an identical NLS-binding groove. Importin α3 uses its greater conformational flexibility to wedge the RCC1 β-propeller flanking the NLS against its lateral surface, preventing steric clashes with its Armadillo-core. Removing the β-propeller, or inserting a linker between NLS and β-propeller, disrupts specificity for importin α3, demonstrating the structural context rather than NLS sequence determines selectivity for isoform 3. We propose importin α3 evolved to recognize topologically complex NLSs that lie next to bulky domains or are masked by quaternary structures.Importin α3 facilitates the nuclear transport of the Ran guanine nucleotide exchange factor RCC1. Here the authors reveal the molecular basis for the selectivity of RCC1 for importin α3 vs the generic importin α1 and discuss the evolution of importin α isoforms.

Recommended Citation

Sankhala, Rajeshwer S.; Lokareddy, Ravi K.; Begum, Salma; Pumroy, Ruth A.; Gillilan, Richard E.; and Cingolani, Gino, "Three-dimensional context rather than NLS amino acid sequence determines importin α subtype specificity for RCC1." (2017). Department of Biochemistry and Molecular Biology Faculty Papers. Paper 128.
https://jdc.jefferson.edu/bmpfp/128

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

PubMed ID

29042532