Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification

K. Shanmugha Rajan; Saurav Aryal; Disha Gajanan Hiregange; Anat Bashan; Hava Madmoni; Mika Olami; Tirza Doniger; Smadar Cohen-Chalamish; Pascal Pescher; Masato Taoka; Yuko Nobe; Aliza Fedorenko; Tanaya Bose; Ella Zimermann; Eric Prina; Noa Aharon-Hefetz; Yitzhak Pilpel; Toshiaki Isobe; Ron Unger; Gerald F. Späth; Ada Yonath; Shulamit Michaeli

doi:10.1016/j.celrep.2024.114203

Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification

K. Shanmugha Rajan, Saurav Aryal, Disha Gajanan Hiregange, Anat Bashan, Hava Madmoni, Mika Olami, Tirza Doniger, Smadar Cohen-Chalamish, Pascal Pescher, Masato Taoka, Yuko Nobe, Aliza Fedorenko, Tanaya Bose, Ella Zimermann, Eric Prina, Noa Aharon-Hefetz, Yitzhak Pilpel, Toshiaki Isobe, Ron Unger, Gerald F. SpäthAda Yonath, Shulamit Michaeli^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

11 Citations (Scopus)

Abstract

Leishmania is the causative agent of cutaneous and visceral diseases affecting millions of individuals worldwide. Pseudouridine (Ψ), the most abundant modification on rRNA, changes during the parasite life cycle. Alterations in the level of a specific Ψ in helix 69 (H69) affected ribosome function. To decipher the molecular mechanism of this phenotype, we determine the structure of ribosomes lacking the single Ψ and its parental strain at ∼2.4–3 Å resolution using cryo-EM. Our findings demonstrate the significance of a single Ψ on H69 to its structure and the importance for its interactions with helix 44 and specific tRNAs. Our study suggests that rRNA modification affects translation of mRNAs carrying codon bias due to selective accommodation of tRNAs by the ribosome. Based on the high-resolution structures, we propose a mechanism explaining how the ribosome selects specific tRNAs.

Original language	English
Article number	114203
Journal	Cell Reports
Volume	43
Issue number	5
Early online date	8 May 2024
DOIs	https://doi.org/10.1016/j.celrep.2024.114203
Publication status	Published - 28 May 2024

Funding

This work was supported by a grant from the Israel Science Foundation (1959/20) to S.M.; ERC 2022-SYG DECOLeishRN grant to S.M., G.F.S., and Y.P.; the Agence Nationale pour la Recherche Labex “Integrative Biology of Emerging Infectious Diseases” contract ANR-10-LABX-62-IBEID and Labex “French Alliance for Parasitology and Health Care” contract ANR-11-LABX-0024 to G.F.S., E.P., and P.P.; the Kimmelman Center for Macromolecular Assemblies to A.Y.; and the Campus France Franco-Israeli Programme Hubert Curien Maimonide 2018 grant to S.M. and G.F.S. K.S.R. is supported by the Dean of Faculty Fellowship, Koshland Prize, and Sir Charles Clore Postdoctoral Fellowship from the Weizmann Institute. S.M. holds the David and Inez Myers Chair in RNA silencing of diseases. A.Y. holds the Martin S. and Helen Kimmel Professorial Chair at the Weizmann Institute of Science. Publisher Copyright: © 2024 The Author(s)

All Science Journal Classification (ASJC) codes

General Biochemistry,Genetics and Molecular Biology

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Rajan, K. S., Aryal, S., Hiregange, D. G., Bashan, A., Madmoni, H., Olami, M., Doniger, T., Cohen-Chalamish, S., Pescher, P., Taoka, M., Nobe, Y., Fedorenko, A., Bose, T., Zimermann, E., Prina, E., Aharon-Hefetz, N., Pilpel, Y., Isobe, T., Unger, R., ... Michaeli, S. (2024). Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification. Cell Reports, 43(5), Article 114203. https://doi.org/10.1016/j.celrep.2024.114203

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title = "Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification",

abstract = "Leishmania is the causative agent of cutaneous and visceral diseases affecting millions of individuals worldwide. Pseudouridine (Ψ), the most abundant modification on rRNA, changes during the parasite life cycle. Alterations in the level of a specific Ψ in helix 69 (H69) affected ribosome function. To decipher the molecular mechanism of this phenotype, we determine the structure of ribosomes lacking the single Ψ and its parental strain at ∼2.4–3 {\AA} resolution using cryo-EM. Our findings demonstrate the significance of a single Ψ on H69 to its structure and the importance for its interactions with helix 44 and specific tRNAs. Our study suggests that rRNA modification affects translation of mRNAs carrying codon bias due to selective accommodation of tRNAs by the ribosome. Based on the high-resolution structures, we propose a mechanism explaining how the ribosome selects specific tRNAs.",

author = "Rajan, \{K. Shanmugha\} and Saurav Aryal and Hiregange, \{Disha Gajanan\} and Anat Bashan and Hava Madmoni and Mika Olami and Tirza Doniger and Smadar Cohen-Chalamish and Pascal Pescher and Masato Taoka and Yuko Nobe and Aliza Fedorenko and Tanaya Bose and Ella Zimermann and Eric Prina and Noa Aharon-Hefetz and Yitzhak Pilpel and Toshiaki Isobe and Ron Unger and Sp{\"a}th, \{Gerald F.\} and Ada Yonath and Shulamit Michaeli",

year = "2024",

month = may,

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doi = "10.1016/j.celrep.2024.114203",

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Rajan, KS, Aryal, S, Hiregange, DG , Bashan, A, Madmoni, H, Olami, M, Doniger, T, Cohen-Chalamish, S, Pescher, P, Taoka, M, Nobe, Y, Fedorenko, A, Bose, T, Zimermann, E, Prina, E, Aharon-Hefetz, N, Pilpel, Y, Isobe, T, Unger, R, Späth, GF, Yonath, A & Michaeli, S 2024, 'Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification', Cell Reports, vol. 43, no. 5, 114203. https://doi.org/10.1016/j.celrep.2024.114203

TY - JOUR

T1 - Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification

AU - Rajan, K. Shanmugha

AU - Aryal, Saurav

AU - Hiregange, Disha Gajanan

AU - Bashan, Anat

AU - Madmoni, Hava

AU - Olami, Mika

AU - Doniger, Tirza

AU - Cohen-Chalamish, Smadar

AU - Pescher, Pascal

AU - Taoka, Masato

AU - Nobe, Yuko

AU - Fedorenko, Aliza

AU - Bose, Tanaya

AU - Zimermann, Ella

AU - Prina, Eric

AU - Aharon-Hefetz, Noa

AU - Pilpel, Yitzhak

AU - Isobe, Toshiaki

AU - Unger, Ron

AU - Späth, Gerald F.

AU - Yonath, Ada

AU - Michaeli, Shulamit

PY - 2024/5/28

Y1 - 2024/5/28

N2 - Leishmania is the causative agent of cutaneous and visceral diseases affecting millions of individuals worldwide. Pseudouridine (Ψ), the most abundant modification on rRNA, changes during the parasite life cycle. Alterations in the level of a specific Ψ in helix 69 (H69) affected ribosome function. To decipher the molecular mechanism of this phenotype, we determine the structure of ribosomes lacking the single Ψ and its parental strain at ∼2.4–3 Å resolution using cryo-EM. Our findings demonstrate the significance of a single Ψ on H69 to its structure and the importance for its interactions with helix 44 and specific tRNAs. Our study suggests that rRNA modification affects translation of mRNAs carrying codon bias due to selective accommodation of tRNAs by the ribosome. Based on the high-resolution structures, we propose a mechanism explaining how the ribosome selects specific tRNAs.

AB - Leishmania is the causative agent of cutaneous and visceral diseases affecting millions of individuals worldwide. Pseudouridine (Ψ), the most abundant modification on rRNA, changes during the parasite life cycle. Alterations in the level of a specific Ψ in helix 69 (H69) affected ribosome function. To decipher the molecular mechanism of this phenotype, we determine the structure of ribosomes lacking the single Ψ and its parental strain at ∼2.4–3 Å resolution using cryo-EM. Our findings demonstrate the significance of a single Ψ on H69 to its structure and the importance for its interactions with helix 44 and specific tRNAs. Our study suggests that rRNA modification affects translation of mRNAs carrying codon bias due to selective accommodation of tRNAs by the ribosome. Based on the high-resolution structures, we propose a mechanism explaining how the ribosome selects specific tRNAs.

UR - https://www.scopus.com/pages/publications/85192245370

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DO - 10.1016/j.celrep.2024.114203

M3 - Article

AN - SCOPUS:85192245370

SN - 2211-1247

VL - 43

JO - Cell Reports

JF - Cell Reports

IS - 5

M1 - 114203

ER -

Structural and mechanistic insights into the function of Leishmania ribosome lacking a single pseudouridine modification

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