Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity
Abstract
The retargeting of protein–DNA specificity, outside of extremely modular DNA binding proteins such as TAL effectors, has generally proved to be quite challenging. Here, we describe structural analyses of five different extensively retargeted variants of a single homing endonuclease, that have been shown to function efficiently in ex vivo and in vivo applications. The redesigned proteins harbor mutations at up to 53 residues (18%) of their amino acid sequence, primarily distributed across the DNA binding surface, making them among the most significantly reengineered ligand-binding proteins to date. Specificity is derived from the combined contributions of DNA-contacting residues and of neighboring residues that influence local structural organization. Changes in specificity are facilitated by the ability of all those residues to readily exchange both form and function. The fidelity of recognition is not precisely correlated with the fraction or total number of residues in the protein–DNA interface that are actually involved in DNA contacts, including directional hydrogen bonds. The plasticity of the DNA-recognition surface of this protein, which allows substantial retargeting of recognition specificity without requiring significant alteration of the surrounding protein architecture, reflects the ability of the corresponding genetic elements to maintain mobility and persistence in the face of genetic driftmore »
- Authors:
-
[1]
- Basic Sciences Division, Fred Hutchinson Cancer Research Center,Seattle, WA (United States)
- Bluebird Bio Inc., Seattle, WA (United States)
- Imperial College of London, Department of Life Sciences, South Kensington Campus, London (United Kingdom)
- Publication Date:
- Research Org.:
- Lawrence Berkeley National Lab (LBNL), Berkeley, CA (United States)
- Sponsoring Org.:
- USDOE Office of Science (SC); National Institutes of Health (NIH) National Institute of General Medical Sciences (NIGMS); Bill and Melinda Gates Foundation; Fred Hutchinson Cancer Center; Bluebird Bio, Inc.
- OSTI Identifier:
- 1625567
- Grant/Contract Number:
- AC02-05CH11231; R01 GM105691
- Resource Type:
- Accepted Manuscript
- Journal Name:
- Nucleic Acids Research
- Additional Journal Information:
- Journal Volume: 45; Journal Issue: 14; Journal ID: ISSN 0305-1048
- Publisher:
- Oxford University Press
- Country of Publication:
- United States
- Language:
- English
- Subject:
- Biochemistry & Molecular Biology
Citation Formats
Werther, Rachel, Hallinan, Jazmine P., Lambert, Abigail R., Havens, Kyle, Pogson, Mark, Jarjour, Jordan, Galizi, Roberto, Windbichler, Nikolai, Crisanti, Andrea, Nolan, Tony, and Stoddard, Barry L. Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity. United States: N. p., 2017.
Web. doi:10.1093/nar/gkx544.
Werther, Rachel, Hallinan, Jazmine P., Lambert, Abigail R., Havens, Kyle, Pogson, Mark, Jarjour, Jordan, Galizi, Roberto, Windbichler, Nikolai, Crisanti, Andrea, Nolan, Tony, & Stoddard, Barry L. Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity. United States. https://doi.org/10.1093/nar/gkx544
Werther, Rachel, Hallinan, Jazmine P., Lambert, Abigail R., Havens, Kyle, Pogson, Mark, Jarjour, Jordan, Galizi, Roberto, Windbichler, Nikolai, Crisanti, Andrea, Nolan, Tony, and Stoddard, Barry L. Tue .
"Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity". United States. https://doi.org/10.1093/nar/gkx544. https://www.osti.gov/servlets/purl/1625567.
@article{osti_1625567,
title = {Crystallographic analyses illustrate significant plasticity and efficient recoding of meganuclease target specificity},
author = {Werther, Rachel and Hallinan, Jazmine P. and Lambert, Abigail R. and Havens, Kyle and Pogson, Mark and Jarjour, Jordan and Galizi, Roberto and Windbichler, Nikolai and Crisanti, Andrea and Nolan, Tony and Stoddard, Barry L.},
abstractNote = {The retargeting of protein–DNA specificity, outside of extremely modular DNA binding proteins such as TAL effectors, has generally proved to be quite challenging. Here, we describe structural analyses of five different extensively retargeted variants of a single homing endonuclease, that have been shown to function efficiently in ex vivo and in vivo applications. The redesigned proteins harbor mutations at up to 53 residues (18%) of their amino acid sequence, primarily distributed across the DNA binding surface, making them among the most significantly reengineered ligand-binding proteins to date. Specificity is derived from the combined contributions of DNA-contacting residues and of neighboring residues that influence local structural organization. Changes in specificity are facilitated by the ability of all those residues to readily exchange both form and function. The fidelity of recognition is not precisely correlated with the fraction or total number of residues in the protein–DNA interface that are actually involved in DNA contacts, including directional hydrogen bonds. The plasticity of the DNA-recognition surface of this protein, which allows substantial retargeting of recognition specificity without requiring significant alteration of the surrounding protein architecture, reflects the ability of the corresponding genetic elements to maintain mobility and persistence in the face of genetic drift within potential host target sites.},
doi = {10.1093/nar/gkx544},
journal = {Nucleic Acids Research},
number = 14,
volume = 45,
place = {United States},
year = {Tue Jun 20 00:00:00 EDT 2017},
month = {Tue Jun 20 00:00:00 EDT 2017}
}
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Tapping natural reservoirs of homing endonucleases for targeted gene modification
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Mutations altering the cleavage specificity of a homing endonuclease
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A combinatorial approach to create artificial homing endonucleases cleaving chosen sequences
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- Nucleic Acids Research, Vol. 34, Issue 22
Web 3DNA--a web server for the analysis, reconstruction, and visualization of three-dimensional nucleic-acid structures
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Efficient targeting of a SCID gene by an engineered single-chain homing endonuclease
journal, July 2009
- Grizot, Sylvestre; Smith, Julianne; Daboussi, Fayza
- Nucleic Acids Research, Vol. 37, Issue 16
High-resolution profiling of homing endonuclease binding and catalytic specificity using yeast surface display
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Reprogramming homing endonuclease specificity through computational design and directed evolution
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Type II restriction endonucleases — a historical perspective and more
journal, June 2016
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On the possibilities and limitations of rational protein design to expand the specificity of restriction enzymes: a case study employing EcoRV as the target
journal, April 2000
- Lanio, Thomas; Jeltsch, Albert; Pingoud, Alfred
- Protein Engineering, Design and Selection, Vol. 13, Issue 4
Heritable targeted mutagenesis in maize using a designed endonuclease
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- The Plant Journal, Vol. 61, Issue 1
Targeted molecular trait stacking in cotton through targeted double‐strand break induction
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- Plant Biotechnology Journal, Vol. 11, Issue 8
Male-sterile maize plants produced by targeted mutagenesis of the cytochrome P450-like gene ( MS26 ) using a re-designed I- Cre I homing endonuclease
journal, November 2013
- Djukanovic, Vesna; Smith, Jeff; Lowe, Keith
- The Plant Journal, Vol. 76, Issue 5
Meganuclease-Driven Targeted Integration in CHO-K1 Cells for the Fast Generation of HTS-Compatible Cell-Based Assays
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Targeted DNA excision in Arabidopsis by a re-engineered homing endonuclease
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