Regulation of mRNA export through API5 and nuclear FGF2 interaction.

Bomin Song,Byung Il Lee,Hyeran Gwak,Hyonchol Jang,Krishnaraj Rajalingam,Sangyoun Park,Se Jin Oh,Seoung Min Bong,Seung-Hyun Bae,Seung-Won Yang,Seungyoon Nam,Sunshin Kim,Tae Woo Kim

doi:10.1093/nar/gkaa335

Abstract

API5 (APoptosis Inhibitor 5) and nuclear FGF2 (Fibroblast Growth Factor 2) are upregulated in various human cancers and are correlated with poor prognosis. Although their physical interaction has been identified, the function related to the resulting complex is unknown. Here, we determined the crystal structure of the API5–FGF2 complex and identified critical residues driving the protein interaction. These findings provided a structural basis for the nuclear localization of the FGF2 isoform lacking a canonical nuclear localization signal and identified a cryptic nuclear localization sequence in FGF2. The interaction between API5 and FGF2 was important for mRNA nuclear export through both the TREX and eIF4E/LRPPRC mRNA export complexes, thus regulating the export of bulk mRNA and specific mRNAs containing eIF4E sensitivity elements, such as c-MYC and cyclin D1. These data show the newly identified molecular function of API5 and nuclear FGF2, and provide a clue to understanding the dynamic regulation of mRNA export.

Highlights

Apoptosis inhibitor 5 (API5, called AAC-11 or FIF) is a nuclear protein that inhibits apoptosis in human cells
Since API5–fibroblast growth factor 2 (FGF2) can interact with the eIF4E/LRPPRC complex in the CRM1-dependent pathway, we investigated whether API5–FGF2 can control the specific mRNAs containing an eIF4E sensitivity element (4E-SE) [32,35]
The structural superposition of the API5–FGF2 and FGF2–FGFR1–heparin complexes with FGF2 as the reference revealed that steric clashes would occur if API5 instead of heparin binds to the FGF2 bound FGF receptors (FGFRs) dimer, implying that API5 is unlikely to affect the role of the FGF2 bound FGFR dimer on the extracellular surface (Supplementary Figure S5)

Summary

Introduction

Apoptosis inhibitor 5 (API5, called AAC-11 or FIF) is a nuclear protein that inhibits apoptosis in human cells. This protein was originally identified in surviving cells after serum deprivation and was later found to be upregulated in various cancers [1,2,3,4]. The crystal structure of API5 suggests that it functions as a protein-protein interaction mediator with HEAT (at the N-terminal half) and ARM-like (at the C-terminal half) repeat protein binding modules [13]. The functions of these interactions are poorly understood, in part due to the lack of structural information

Methods

Results

Conclusion