Nuclear export receptor CRM1 recognizes diverse conformations in nuclear export signals

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Abstract

Nuclear export receptor CRM1 binds highly variable nuclear export signals (NESs) in hundreds of different cargoes. Previously we have shown that CRM1 binds NESs in both polypeptide orientations (Fung et al., 2015). Here, we show crystal structures of CRM1 bound to eight additional NESs which reveal diverse conformations that range from loop-like to all-helix, which occupy different extents of the invariant NES-binding groove. Analysis of all NES structures show 5-6 distinct backbone conformations where the only conserved secondary structural element is one turn of helix that binds the central portion of the CRM1 groove. All NESs also participate in main chain hydrogen bonding with human CRM1 Lys568 side chain, which acts as a specificity filter that prevents binding of non-NES peptides. The large conformational range of NES backbones explains the lack of a fixed pattern for its 3-5 hydrophobic anchor residues, which in turn explains the large array of peptide sequences that can function as NESs.

DOI: http://dx.doi.org/10.7554/eLife.23961.001

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NES consensus redefined by structures of PKI-type and Rev-type nuclear export signals bound to CRM1.

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Classic nuclear export signals (NESs) confer CRM1-dependent nuclear export. Here we present crystal structures of the RanGTP-CRM1 complex alone and bound to the prototypic PKI or HIV-1 Rev NESs. These NESs differ markedly in the spacing of their key hydrophobic (Φ) residues, yet CRM1 recognizes them with the same rigid set of five Φ pockets. The different Φ spacings are compensated for by different conformations of the bound NESs: in the case of PKI, an α-helical conformation, and in the case of Rev, an extended conformation with a critical proline docking into a Φ pocket. NMR analyses of CRM1-bound and CRM1-free PKI NES suggest that CRM1 selects NES conformers that pre-exist in solution. Our data lead to a new structure-based NES consensus, and explain why NESs differ in their affinities for CRM1 and why supraphysiological NESs bind the exportin so tightly.

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Author and article information

Contributors

Mingjie Zhang: Role: Reviewing editor

Journal

Journal ID (nlm-ta): eLife

Journal ID (iso-abbrev): Elife

Journal ID (hwp): eLife

Journal ID (publisher-id): eLife

Title: eLife

Publisher: eLife Sciences Publications, Ltd

ISSN (Electronic): 2050-084X

Publication date (Electronic, pub): 10 March 2017

Publication date Collection: 2017

Volume: 6

Electronic Location Identifier: e23961

Affiliations

[1]deptDepartment of Pharmacology , University of Texas Southwestern Medical Center , Dallas, United States

[2]The Hong Kong University of Science and Technology , China

[3]The Hong Kong University of Science and Technology , China

Author notes

yuhmin.chook@ 123456utsouthwestern.edu

Author information

Ho Yee Joyce Fung http://orcid.org/0000-0002-0502-1957

Yuh Min Chook http://orcid.org/0000-0002-4974-0726

Article

Publisher ID: 23961

DOI: 10.7554/eLife.23961

PMC ID: 5358978

PubMed ID: 28282025

SO-VID: 14ef8582-0d8a-44e2-a4f6-217657bc1261

License:

This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.

History

Date received : 06 December 2016

Date accepted : 09 March 2017

Funding

Funded by: FundRef http://dx.doi.org/10.13039/100000011, Howard Hughes Medical Institute;

Award ID: International Student Research fellow

Award Recipient : Ho Yee Joyce Fung

Funded by: FundRef http://dx.doi.org/10.13039/501100001692, Croucher Foundation;

Award ID: Graduate Student Scholarship

Award Recipient : Ho Yee Joyce Fung

Funded by: FundRef http://dx.doi.org/10.13039/100004917, Cancer Prevention and Research Institute of Texas;

Award ID: RP120352