Eukaryotic initiation factor 4A-III

Definition:

ATP-dependent RNA helicase. Involved in pre-mRNA splicing as component of the spliceosome. Core component of the splicing-dependent multiprotein exon junction complex (EJC) deposited at splice junctions on mRNAs. The EJC is a dynamic structure consisting of core proteins and several peripheral nuclear and cytoplasmic associated factors that join the complex only transiently either during EJC assembly or during subsequent mRNA metabolism. The EJC marks the position of the exon-exon junction in the mature mRNA for the gene expression machinery and the core components remain bound to spliced mRNAs throughout all stages of mRNA metabolism thereby influencing downstream processes including nuclear mRNA export, subcellular mRNA localization, translation efficiency and nonsense-mediated mRNA decay (NMD). Its RNA-dependent ATPase and RNA-helicase activities are induced by CASC3, but abolished in presence of the MAGOH-RBM8A heterodimer, thereby trapping the ATP-bound EJC core onto spliced mRNA in a stable conformation. The inhibition of ATPase activity by the MAGOH-RBM8A heterodimer increases the RNA-binding affinity of the EJC. Involved in translational enhancement of spliced mRNAs after formation of the 80S ribosome complex. Binds spliced mRNA in sequence-independent manner, 20-24 nucleotides upstream of mRNA exon-exon junctions. Shows higher affinity for single-stranded RNA in an ATP-bound core EJC complex than after the ATP is hydrolyzed. Involved in the splicing modulation of BCL2L1/Bcl-X (and probably other apoptotic genes); specifically inhibits formation of proapoptotic isoforms such as Bcl-X(S); the function is different from the established EJC assembly. Involved in craniofacial development.

References:

[1]. Klaus H Nielsen, et al. Mechanism of ATP turnover inhibition in the EJC. RNA. 2009 Jan;15(1):67-75. [Content Brief]

[2]. Xiaofeng Zhang, et al. An Atomic Structure of the Human Spliceosome. Cell. 2017 May 18;169(5):918-929.e14. [Content Brief]

[3]. Xiechao Zhan, et al. Structure of a human catalytic step I spliceosome. Science. 2018 Feb 2;359(6375):537-545. [Content Brief]

[4]. Christian G Noble, et al. MLN51 stimulates the RNA-helicase activity of eIF4AIII. PLoS One. 2007 Mar 21;2(3):e303. [Content Brief]

[5]. Karl Bertram, et al. Cryo-EM structure of a human spliceosome activated for step 2 of splicing. Nature. 2017 Feb 16;542(7641):318-323. [Content Brief]

[6]. Thomas Ø Tange, et al. Biochemical analysis of the EJC reveals two new factors and a stable tetrameric protein core. RNA. 2005 Dec;11(12):1869-83. [Content Brief]

[7]. Fulvia Bono, et al. The crystal structure of the exon junction complex reveals how it maintains a stable grip on mRNA. Cell. 2006 Aug 25;126(4):713-25. [Content Brief]

[8]. Hyung Chul Lee, et al. Exon junction complex enhances translation of spliced mRNAs at multiple steps. Biochem Biophys Res Commun. 2009 Jul 3;384(3):334-40. [Content Brief]

[9]. Lionel Ballut, et al. The exon junction core complex is locked onto RNA by inhibition of eIF4AIII ATPase activity. Nat Struct Mol Biol. 2005 Oct;12(10):861-9. [Content Brief]

[10]. Christian B F Andersen, et al. Structure of the exon junction core complex with a trapped DEAD-box ATPase bound to RNA. Science. 2006 Sep 29;313(5795):1968-72. [Content Brief]

[11]. Melissa S Jurica, et al. Purification and characterization of native spliceosomes suitable for three-dimensional structural analysis. RNA. 2002 Apr;8(4):426-39. [Content Brief]

[12]. Isabelle Barbosa, et al. Human CWC22 escorts the helicase eIF4AIII to spliceosomes and promotes exon junction complex assembly. Nat Struct Mol Biol. 2012 Oct;19(10):983-90. [Content Brief]

[13]. Toshiharu Shibuya, et al. eIF4AIII binds spliced mRNA in the exon junction complex and is essential for nonsense-mediated decay. Nat Struct Mol Biol. 2004 Apr;11(4):346-51. [Content Brief]

[14]. Laetitia Michelle, et al. Proteins associated with the exon junction complex also control the alternative splicing of apoptotic regulators. Mol Cell Biol. 2012 Mar;32(5):954-67. [Content Brief]

[15]. Gretel Buchwald, et al. Insights into the recruitment of the NMD machinery from the crystal structure of a core EJC-UPF3b complex. Proc Natl Acad Sci U S A. 2010 Jun 1;107(22):10050-5. [Content Brief]

[16]. Niels H Gehring, et al. Exon-junction complex components specify distinct routes of nonsense-mediated mRNA decay with differential cofactor requirements. Mol Cell. 2005 Oct 7;20(1):65-75. [Content Brief]

[17]. Francine P Favaro, et al. A noncoding expansion in EIF4A3 causes Richieri-Costa-Pereira syndrome, a craniofacial disorder associated with limb defects. Am J Hum Genet. 2014 Jan 2;94(1):120-8. [Content Brief]

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