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Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase

The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of the Elongation Factor-like...

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Autores principales: Pérez-Juárez, Jesús, Tapia-Vieyra, Juana Virginia, Gutiérrez-Magdaleno, Gabriel, Sánchez-Puig, Nuria
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405973/
https://www.ncbi.nlm.nih.gov/pubmed/36009035
http://dx.doi.org/10.3390/biom12081141
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author Pérez-Juárez, Jesús
Tapia-Vieyra, Juana Virginia
Gutiérrez-Magdaleno, Gabriel
Sánchez-Puig, Nuria
author_facet Pérez-Juárez, Jesús
Tapia-Vieyra, Juana Virginia
Gutiérrez-Magdaleno, Gabriel
Sánchez-Puig, Nuria
author_sort Pérez-Juárez, Jesús
collection PubMed
description The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of the Elongation Factor-like 1 (human EFL1, yeast Efl1) GTPase and its effector, the Shwachman-Bodian-Diamond syndrome protein (human SBDS, yeast Sdo1). Mutations in these proteins prevent the release of eIF6 and cause a disease known as Shwachman–Diamond Syndrome (SDS). While some mutations in EFL1 or SBDS result in insufficient proteins to meet the cell production of mature large ribosomal subunits, others do not affect the expression levels with unclear molecular defects. We studied the functional consequences of one such mutation using Saccharomyces cerevisiae Efl1 R1086Q, equivalent to human EFL1 R1095Q described in SDS patients. We characterised the enzyme kinetics and energetic basis outlining the recognition of this mutant to guanine nucleotides and Sdo1, and their interplay in solution. From our data, we propose a model where the conformational change in Efl1 depends on a long-distance network of interactions that are disrupted in mutant R1086Q, whereby Sdo1 and the guanine nucleotides no longer elicit the conformational changes previously described in the wild-type protein. These findings point to the molecular malfunction of an EFL1 mutant and its possible impact on SDS pathology.
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spelling pubmed-94059732022-08-26 Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase Pérez-Juárez, Jesús Tapia-Vieyra, Juana Virginia Gutiérrez-Magdaleno, Gabriel Sánchez-Puig, Nuria Biomolecules Article The final maturation step of the 60S ribosomal subunit requires the release of eukaryotic translation initiation factor 6 (human eIF6, yeast Tif6) to enter the pool of mature ribosomes capable of engaging in translation. This process is mediated by the concerted action of the Elongation Factor-like 1 (human EFL1, yeast Efl1) GTPase and its effector, the Shwachman-Bodian-Diamond syndrome protein (human SBDS, yeast Sdo1). Mutations in these proteins prevent the release of eIF6 and cause a disease known as Shwachman–Diamond Syndrome (SDS). While some mutations in EFL1 or SBDS result in insufficient proteins to meet the cell production of mature large ribosomal subunits, others do not affect the expression levels with unclear molecular defects. We studied the functional consequences of one such mutation using Saccharomyces cerevisiae Efl1 R1086Q, equivalent to human EFL1 R1095Q described in SDS patients. We characterised the enzyme kinetics and energetic basis outlining the recognition of this mutant to guanine nucleotides and Sdo1, and their interplay in solution. From our data, we propose a model where the conformational change in Efl1 depends on a long-distance network of interactions that are disrupted in mutant R1086Q, whereby Sdo1 and the guanine nucleotides no longer elicit the conformational changes previously described in the wild-type protein. These findings point to the molecular malfunction of an EFL1 mutant and its possible impact on SDS pathology. MDPI 2022-08-19 /pmc/articles/PMC9405973/ /pubmed/36009035 http://dx.doi.org/10.3390/biom12081141 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pérez-Juárez, Jesús
Tapia-Vieyra, Juana Virginia
Gutiérrez-Magdaleno, Gabriel
Sánchez-Puig, Nuria
Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title_full Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title_fullStr Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title_full_unstemmed Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title_short Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase
title_sort altered conformational landscape upon sensing guanine nucleotides in a disease mutant of elongation factor-like 1 (efl1) gtpase
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9405973/
https://www.ncbi.nlm.nih.gov/pubmed/36009035
http://dx.doi.org/10.3390/biom12081141
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