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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MDPI AG
2022-08-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/8/1141 |
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| author | Jesús Pérez-Juárez Juana Virginia Tapia-Vieyra Gabriel Gutiérrez-Magdaleno Nuria Sánchez-Puig |
| author_facet | Jesús Pérez-Juárez Juana Virginia Tapia-Vieyra Gabriel Gutiérrez-Magdaleno Nuria Sánchez-Puig |
| author_sort | Jesús Pérez-Juárez |
| collection | DOAJ |
| 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 <i>Saccharomyces cerevisiae</i> 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. |
| first_indexed | 2024-03-09T10:00:46Z |
| format | Article |
| id | doaj.art-c6fd9514ac5346028adfa12900a853bd |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T10:00:46Z |
| publishDate | 2022-08-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-c6fd9514ac5346028adfa12900a853bd2023-12-01T23:29:21ZengMDPI AGBiomolecules2218-273X2022-08-01128114110.3390/biom12081141Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPaseJesús Pérez-Juárez0Juana Virginia Tapia-Vieyra1Gabriel Gutiérrez-Magdaleno2Nuria Sánchez-Puig3Departamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de Mexico 04510, MexicoDepartamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de Mexico 04510, MexicoDivisión de Ciencias Naturales e Ingeniería, Universidad Autónoma Metropolitana, Unidad Cuajimalpan Avenida Vasco de Quiroga 4871, Ciudad de Mexico 05348, MexicoDepartamento de Química de Biomacromoléculas, Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior s/n, Ciudad Universitaria, Ciudad de Mexico 04510, MexicoThe 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 <i>Saccharomyces cerevisiae</i> 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.https://www.mdpi.com/2218-273X/12/8/1141conformational changeEFL1guanine nucleotidesITCmagnesium ionsSBDS |
| spellingShingle | Jesús Pérez-Juárez Juana Virginia Tapia-Vieyra Gabriel Gutiérrez-Magdaleno Nuria Sánchez-Puig Altered Conformational Landscape upon Sensing Guanine Nucleotides in a Disease Mutant of Elongation Factor-like 1 (EFL1) GTPase Biomolecules conformational change EFL1 guanine nucleotides ITC magnesium ions SBDS |
| 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 | conformational change EFL1 guanine nucleotides ITC magnesium ions SBDS |
| url | https://www.mdpi.com/2218-273X/12/8/1141 |
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