Dynamic interaction network involving the conserved intrinsically disordered regions in human eIF5

Paul, Eleanor Elise; Lin, Kay Ying; Gamble, Nathan; Tsai, Amy Wei-Lun; Swan, Simon H.K.; Yang, Yu; Doran, Matthew; Marintchev, Assen

doi:10.1016/j.bpc.2021.106740

Cited by 5 publications

(27 citation statements)

References 37 publications

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“…While eIF2β K2 was not resolved in the crystal structure, the authors proposed that K2 could be interacting with the negatively charged surface formed by AA boxes 1 and 2 of eIF5 ( 189 ). In good agreement with this study, mutational analysis ( 82 , 83 ) and NMR studies ( 141 , 191 ) have shown that AA box 2 plays a central role in the eIF5–eIF2β interaction. In mammals, phosphorylation of the AA box 2 in eIF5 by Casein Kinase 2 (CK2) promotes protein synthesis and cell proliferation ( 192 ), mediated by increasing the eIF5 affinity for eIF2β ( 191 ).…”

Section: Discussionsupporting

confidence: 90%

“…In good agreement with this study, mutational analysis ( 82 , 83 ) and NMR studies ( 141 , 191 ) have shown that AA box 2 plays a central role in the eIF5–eIF2β interaction. In mammals, phosphorylation of the AA box 2 in eIF5 by Casein Kinase 2 (CK2) promotes protein synthesis and cell proliferation ( 192 ), mediated by increasing the eIF5 affinity for eIF2β ( 191 ). Recently, the complex of eIF2 and eIF2B has been studied by cryo-electron microscopy, but the eIF2β−NTT could not be resolved ( 125 , 140 ).…”

Section: Discussionsupporting

confidence: 90%

“…The electrostatic surface potentials, the surface Kyte-Doolittle hydrophobicity, and evolutionary conservation of surface residues are shown. In these analyses, the loop and C-terminal α-helix in human eIF5 (depicted in ribbon representation) are not included as they are highly flexible in solution ( 191 ). All structures are shown in the same orientations as in (B).…”

Section: Discussionmentioning

confidence: 99%

“…AA box 2 establishes an extended loop that folds back on the eIF5 W2/HEAT3 surface. However, NMR data indicate that even in eIF5, AA box 2 is disordered in solution and only dynamically contacts the W2/HEAT3 surface ( 191 ). Combined with the missing electron density in the other three W2/HEAT3 domain structures, this suggests high flexibility of this region in AA box 2.…”

Section: Discussionmentioning

confidence: 99%

“…The C-terminal AA box 2 may only transiently fold back on W2/HEAT3 (as seen in eIF5) and may populate multiple conformational states of which each can promote binding to specific interaction partners ( 191 ). Future investigations are required to decipher if this transient nature is key for how the eIF4G, DAP5, eIF5 and eIF2Bϵ W2/HEAT3 domains selectively interact with their binding partners.…”

Section: Discussionmentioning

confidence: 99%

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

Stöppler

Marintchev

Arthanari

2022

Nucleic Acids Research

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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.

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