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Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases

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Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases. / Byrne, Robert T.; Jenkins, Huw T.; Peters, Daniel T.; Whelan, Fiona; Stowell, James; Aziz, Naveed; Kasatsky, Pavel; Rodnina, Marina V.; Koonin, Eugene V.; Konevega, Andrey L.; Antson, Alfred A.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 112, No. 19, 12.05.2015, p. 6033-6037.

Research output: Contribution to journalArticlepeer-review

Harvard

Byrne, RT, Jenkins, HT, Peters, DT, Whelan, F, Stowell, J, Aziz, N, Kasatsky, P, Rodnina, MV, Koonin, EV, Konevega, AL & Antson, AA 2015, 'Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases', Proceedings of the National Academy of Sciences of the United States of America, vol. 112, no. 19, pp. 6033-6037. https://doi.org/10.1073/pnas.1500161112

APA

Byrne, R. T., Jenkins, H. T., Peters, D. T., Whelan, F., Stowell, J., Aziz, N., Kasatsky, P., Rodnina, M. V., Koonin, E. V., Konevega, A. L., & Antson, A. A. (2015). Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases. Proceedings of the National Academy of Sciences of the United States of America, 112(19), 6033-6037. https://doi.org/10.1073/pnas.1500161112

Vancouver

Byrne RT, Jenkins HT, Peters DT, Whelan F, Stowell J, Aziz N et al. Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases. Proceedings of the National Academy of Sciences of the United States of America. 2015 May 12;112(19):6033-6037. https://doi.org/10.1073/pnas.1500161112

Author

Byrne, Robert T. ; Jenkins, Huw T. ; Peters, Daniel T. ; Whelan, Fiona ; Stowell, James ; Aziz, Naveed ; Kasatsky, Pavel ; Rodnina, Marina V. ; Koonin, Eugene V. ; Konevega, Andrey L. ; Antson, Alfred A. / Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases. In: Proceedings of the National Academy of Sciences of the United States of America. 2015 ; Vol. 112, No. 19. pp. 6033-6037.

Bibtex - Download

@article{32ce99da830f40c0884bc34f8182cad7,
title = "Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases",
abstract = "The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160° rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ({"}binding signatures{"}) together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal {"}recognition{"} domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.",
keywords = "Dihydrouridine synthase, Protein-RNA interaction, Substrate specificity, TRNA modification, X-ray crystallography",
author = "Byrne, {Robert T.} and Jenkins, {Huw T.} and Peters, {Daniel T.} and Fiona Whelan and James Stowell and Naveed Aziz and Pavel Kasatsky and Rodnina, {Marina V.} and Koonin, {Eugene V.} and Konevega, {Andrey L.} and Antson, {Alfred A.}",
year = "2015",
month = may,
day = "12",
doi = "10.1073/pnas.1500161112",
language = "English",
volume = "112",
pages = "6033--6037",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "19",

}

RIS (suitable for import to EndNote) - Download

TY - JOUR

T1 - Major reorientation of tRNA substrates defines specificity of dihydrouridine synthases

AU - Byrne, Robert T.

AU - Jenkins, Huw T.

AU - Peters, Daniel T.

AU - Whelan, Fiona

AU - Stowell, James

AU - Aziz, Naveed

AU - Kasatsky, Pavel

AU - Rodnina, Marina V.

AU - Koonin, Eugene V.

AU - Konevega, Andrey L.

AU - Antson, Alfred A.

PY - 2015/5/12

Y1 - 2015/5/12

N2 - The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160° rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ("binding signatures") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal "recognition" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.

AB - The reduction of specific uridines to dihydrouridine is one of the most common modifications in tRNA. Increased levels of the dihydrouridine modification are associated with cancer. Dihydrouridine synthases (Dus) from different subfamilies selectively reduce distinct uridines, located at spatially unique positions of folded tRNA, into dihydrouridine. Because the catalytic center of all Dus enzymes is conserved, it is unclear how the same protein fold can be reprogrammed to ensure that nucleotides exposed at spatially distinct faces of tRNA can be accommodated in the same active site. We show that the Escherichia coli DusC is specific toward U16 of tRNA. Unexpectedly, crystal structures of DusC complexes with tRNA(Phe) and tRNA(Trp) show that Dus subfamilies that selectively modify U16 or U20 in tRNA adopt identical folds but bind their respective tRNA substrates in an almost reverse orientation that differs by a 160° rotation. The tRNA docking orientation appears to be guided by subfamily-specific clusters of amino acids ("binding signatures") together with differences in the shape of the positively charged tRNA-binding surfaces. tRNA orientations are further constrained by positional differences between the C-terminal "recognition" domains. The exquisite substrate specificity of Dus enzymes is therefore controlled by a relatively simple mechanism involving major reorientation of the whole tRNA molecule. Such reprogramming of the enzymatic specificity appears to be a unique evolutionary solution for altering tRNA recognition by the same protein fold.

KW - Dihydrouridine synthase

KW - Protein-RNA interaction

KW - Substrate specificity

KW - TRNA modification

KW - X-ray crystallography

UR - http://www.scopus.com/inward/record.url?scp=84929190405&partnerID=8YFLogxK

U2 - 10.1073/pnas.1500161112

DO - 10.1073/pnas.1500161112

M3 - Article

C2 - 25902496

AN - SCOPUS:84929190405

VL - 112

SP - 6033

EP - 6037

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 19

ER -