The metaphorical swiss army knife: The multitude and diverse roles of HEAT domains in eukaryotic translation initiation

Abstract

Biomolecular associations forged by specific interaction among structural scaffolds are fundamental to the control and regulation of cell processes. One such structural architecture, characterized by HEAT repeats, is involved in a multitude of cellular processes, including intracellular transport, signaling, and protein synthesis. Here, we review the multitude and versatility of HEAT domains in the regulation of mRNA translation initiation. Structural and cellular biology approaches, as well as several biophysical studies, have revealed that a number of HEAT domain-mediated interactions with a host of protein factors and RNAs coordinate translation initiation. We describe the basic structural architecture of HEAT domains and briefly introduce examples of the cellular processes they dictate, including nuclear transport by importin and RNA degradation. We then focus on proteins in the translation initiation system featuring HEAT domains, specifically the HEAT domains of eIF4G, DAP5, eIF5, and eIF2Bϵ. Comparative analysis of their remarkably versatile interactions, including protein–protein and protein–RNA recognition, reveal the functional importance of flexible regions within these HEAT domains. Here we outline how HEAT domains orchestrate fundamental aspects of translation initiation and highlight open mechanistic questions in the area.

Specific mechanisms of translation initiation in higher eukaryotes: the eIF4G2 story

“…Both homologues have three HEAT domains: MIF4G, MA3, and W2 (Figure 2A). The X-ray diffraction data have been obtained for all three HEAT domains and the eIF4E-binding site of eIF4G1 (Friedrich et al 2022), and for MIF4G (residues 61-323) (Virgili et al 2013), MA3, and W2 domains (540-897) of eIF4G2 (Figure 2A) (Fan et al 2010;Liberman et al 2008). Maximum structural similarity is observed between the MIF4G domains of eIF4G1 and eIF4G2 (39% sequence identity, 59% similarity; see Figure 2B) (Virgili et al 2013), which are both responsible for the interaction with eIF4A.…”

“…There is a recent detailed review of eIF4G1 and eIF4G2 structures ( Friedrich et al 2022 ), therefore we will just briefly outline some important points. Structural analysis of full-length eIF4G1 (the longest isoform consists of 1599 amino acids in humans) and eIF4G2 (907 amino acids in humans) has not yet been performed.…”

“…2 A). The X-ray diffraction data have been obtained for all three HEAT domains and the eIF4E-binding site of eIF4G1 ( Friedrich et al 2022 ), and for MIF4G (residues 61–323) ( Virgili et al 2013 ), MA3, and W2 domains (540–897) of eIF4G2 ( Fig. 2 A; Liberman et al 2008 ; Fan et al 2010 ).…”

Structure ofToxoplasma gondiiglideosome-associated connector suggests a role as an elastic element in actomyosin force generation for gliding motility

“…Given the elastic characteristics of solenoid domains 22,23,[27][28][29][30][31][32][33][34][35][36] and examples of helical repeat proteins, like the catenin core complex in adherens junctions 37,38 and talin in focal adhesions 39,40 , it seems plausible that GAC may act as a spring-like connection between the short (~100 nm) actin filaments [41][42][43] and the adhesion complex that is formed during gliding motility and invasion (Fig. 7).…”

RNAi-Mediated Knockdown of Acidic Ribosomal Stalk Protein P1 Arrests Egg Development in Adult Female Yellow Fever Mosquitoes, Aedes aegypti

“…The N-terminal domain of GCN1 is necessary for robust ribosome binding [39][40][41]. Downstream of this N-terminal domain is a region containing several HEAT repeats, repetitive arrays of short amphiphilic α-helices, that are involved in the formation of protein-protein interactions (see Figure 2A) [42,43]. The C-terminal domain of GCN1 also interacts with colliding ribosomes and mediates the interaction between GCN1 and GCN2 [41,44].…”