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Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries
COSTBI-1331; NO. OF PAGES 2
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries Fre´de´ric H-T Allain and Hashim M Al-Hashimi Current Opinion in Structural Biology 2015, 30:xx–yy
http://dx.doi.org/10.1016/j.sbi.2015.03.006 0959-440X/# 2015 Elsevier Ltd. All rights reserved.
Fre´de´ric H-T Allain Institute for Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland e-mail: [email protected] Fre´de´ric H-T Allain trained as a chemist at the Ecole Normale Superieure in Paris becoming a structural biologist during his PhD at the MRCLMB in Cambridge with Gabriele Varani (UK). After two post-docs with Juli Feigon and later Doug Black in UCLA, California, he started his lab at the ETH Zurich, Switzerland in 2001 as an assistant professor. He is now Professor of Biomolecular NMR. His lab is best known for the solution structures of several RNA binding proteins bound to RNA, more particularly alternative-splicing factors. Over the years the numerous structures solved in the lab revealed the unexpected large variety of RNA recognitions and modes of action of small RNA binding domains.
Hashim M Al-Hashimi Department of Biochemistry and Chemistry, Duke University School of Medicine, Durham, NC 27710, USA e-mail: [email protected] Hashim M Al-Hashimi trained as a biophysical chemist at Yale University with James Prestegard where he contributed to the development of NMR residual dipolar couplings based methods for studying the structure and dynamics of proteins. After two years as a postdoctoral fellow with Dinshaw Patel at the Memorial Sloane-Kettering Cancer Center in New York, where he focused on the development and application of NMR methods to study the structure and dynamics of nucleic acids, he started his lab at the University of Michigan in 2002 as an Assistant Professor of Chemistry and Biophysics. In 2014, he relocated to Duke University where is currently Professor of Biochemistry and Chemistry. His lab is best known for the development and application of NMR methods for characterizing the dynamic properties of DNA and RNA.
www.sciencedirect.com
It would be difficult to imagine that the field of nucleic acid structural biology would be growing at an even more rapid pace than it did just a couple of years ago either conceptually or technologically — but indeed, it is, and this issue of Current Opinion in Structural Biology explains why and how. In many cases, the catalysts of these advances are new technologies that are allowing us to learn something new about the structural properties of nucleic acids and their biology that would otherwise have been impossible or very difficult by conventional methods. Other advances are arising from continued painstaking efforts that are seeking to unlock the most inner secrets of nucleic acids. This issue of Current Opinion in Structural Biology captures these advances, from new developments in technologies that can provide new insights into the architecture of large RNAs and their dynamics, to new insights into how nucleic acids are recognized by proteins and small molecules, and the new groundbreaking technology, CRISPR-Cas, which is transforming biology and medicine. This issue reports two different approaches for recognizing single stranded nucleic acids. Ramos and coworkers report recent structural findings on how hnRNP K homology domain (KH) recognize single-stranded RNA. While most KH domains were found to recognize C-containing or A-containing RNA, the Ramos group could show with one KH-domain of KSRP that Grich sequence could also be sequence-specifically bound to such fold when widening the binding groove of the domain. They additionally review recent findings on extended KH domain and in particular on RNA recognition and dimerization of STAR domains. Single-stranded DNA binding is also reviewed by Campagne and coworkers in the context of sigma factor DNA recognition. This review presents recent structural findings on how specific sigma factors can target a subset of promotors independently and using a different recognition mechanism than the housekeeping sigma factors. The review also touches upon the regulation of transcription and how a two-component system can mimic sigma factor to activate transcription. Structure determination of large non-coding RNA presents a considerable challenge because they can be flexible and difficult to crystallize for X-ray crystallography or press the size-limits of NMR spectroscopy. Wang and colleagues review how small angle X-ray scattering (SAXS) is making into possible to transform an RNA secondary structure, which is increasingly accessible by ‘chemical probing’ technologies, into a 3D conformation Current Opinion in Structural Biology 2015, 30:1–2
Please cite this article in press as: Allain FH-T, Al-Hashimi HM: Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries, Curr Opin Struct Biol (2015), http://dx.doi.org/10.1016/j.sbi.2015.03.006
COSTBI-1331; NO. OF PAGES 2
2 Nucleic acids
outlining the overall RNA fold. Thus, by combining topological constraints encoded by an RNA secondary structure, with the powerful information regarding overall shape obtained by SAXS, it is now increasingly possible to determine the tertiary folds of large non-coding RNAs. These developments help to narrow the current divide between RNA secondary and tertiary structure. Nucleic acids are highly flexible and their structures often have to contort in specific ways when carrying out their biological functions. Zhang and colleagues review a growing repertoire of NMR techniques that are making it possible to characterize dynamic excursions away from energetically stable ‘ground states’ of RNA towards higher energy, low populated, and short-lived ‘excited states’ that are difficult to characterize by conventional methods. These studies suggest that most RNAs do not adopt a single secondary structure, but rather, are in constant rapid motion with related secondary structures. They review how these rapid RNA switches can be integrated into a wide variety of circuits to achieve different regulatory functions. Riboswitches are an example par excellence of non-coding RNAs that use shape-shifting to carry out regulatory functions in gene expression regulation. The working model has been based on aptamer domains switching between a ligand-free or ligand-bound conformation. Schwalbe and coworkers review recent studies that are challenging this simple two-state model to reveal higher order complexities. These studies suggest that conformational heterogeneity, particularly in the ligand free RNA, provide a basis for fine-tuning gene regulation and for achieving more sensitivity to multiple environmental inputs. Achieving a truly predictive understanding of how RNA carries out its biological function ultimately requires
Current Opinion in Structural Biology 2015, 30:1–2
models that can predict RNA folding behavior based on first principles. Herschlag and coworkers review an approach that seeks to deconstruct RNA into basic building components, such as helix–junction–helix and tertiary motifs, and to obtain unprecedented insights into the structural, dynamic and energetic properties of these components by applying new biophysical methods that make it possible to describe the structure of such components in terms of statistical ensembles. These advances provide a basis for reconstituting RNA folding from first principles, and to reveal hitherto unknown forces and interactions that may play important roles in RNA folding and function. A major breakthrough in recent year in both fundamental research and biotechnology is certainly the discovery of the CRISPR-Cas bacterial defense system and its application for genome editing. Doudna and coworkers superbly review the recent structural findings on the different types of CRISPR-Cas. The review illustrates the huge diversity of organization, the large conformational changes and the interplay between double-stranded and single-stranded nucleic acid recognition of the different types of CRISPR-Cas. The importance of the structural knowledge for the genome editing is of course touched upon. Non-coding RNAs can potentially revolutionize the scope of drug discovery by providing new targets for treating human diseases for which there are presently no suitable druggable protein targets. Efforts to target RNAs using RNA-based therapeutics have been road blocked by severe delivery limitations. Small molecules provide an alternative approach for targeting RNA that has not been fully explored. Varani and coworkers review recent progress in the development and application of methods for targeting a wide range of disease-relevant non-coding RNAs with small molecules.
www.sciencedirect.com
Please cite this article in press as: Allain FH-T, Al-Hashimi HM: Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries, Curr Opin Struct Biol (2015), http://dx.doi.org/10.1016/j.sbi.2015.03.006
Available online at www.sciencedirect.com
ScienceDirect Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries Fre´de´ric H-T Allain and Hashim M Al-Hashimi Current Opinion in Structural Biology 2015, 30:xx–yy
http://dx.doi.org/10.1016/j.sbi.2015.03.006 0959-440X/# 2015 Elsevier Ltd. All rights reserved.
Fre´de´ric H-T Allain Institute for Molecular Biology and Biophysics, ETH Zurich, CH-8093 Zurich, Switzerland e-mail: [email protected] Fre´de´ric H-T Allain trained as a chemist at the Ecole Normale Superieure in Paris becoming a structural biologist during his PhD at the MRCLMB in Cambridge with Gabriele Varani (UK). After two post-docs with Juli Feigon and later Doug Black in UCLA, California, he started his lab at the ETH Zurich, Switzerland in 2001 as an assistant professor. He is now Professor of Biomolecular NMR. His lab is best known for the solution structures of several RNA binding proteins bound to RNA, more particularly alternative-splicing factors. Over the years the numerous structures solved in the lab revealed the unexpected large variety of RNA recognitions and modes of action of small RNA binding domains.
Hashim M Al-Hashimi Department of Biochemistry and Chemistry, Duke University School of Medicine, Durham, NC 27710, USA e-mail: [email protected] Hashim M Al-Hashimi trained as a biophysical chemist at Yale University with James Prestegard where he contributed to the development of NMR residual dipolar couplings based methods for studying the structure and dynamics of proteins. After two years as a postdoctoral fellow with Dinshaw Patel at the Memorial Sloane-Kettering Cancer Center in New York, where he focused on the development and application of NMR methods to study the structure and dynamics of nucleic acids, he started his lab at the University of Michigan in 2002 as an Assistant Professor of Chemistry and Biophysics. In 2014, he relocated to Duke University where is currently Professor of Biochemistry and Chemistry. His lab is best known for the development and application of NMR methods for characterizing the dynamic properties of DNA and RNA.
www.sciencedirect.com
It would be difficult to imagine that the field of nucleic acid structural biology would be growing at an even more rapid pace than it did just a couple of years ago either conceptually or technologically — but indeed, it is, and this issue of Current Opinion in Structural Biology explains why and how. In many cases, the catalysts of these advances are new technologies that are allowing us to learn something new about the structural properties of nucleic acids and their biology that would otherwise have been impossible or very difficult by conventional methods. Other advances are arising from continued painstaking efforts that are seeking to unlock the most inner secrets of nucleic acids. This issue of Current Opinion in Structural Biology captures these advances, from new developments in technologies that can provide new insights into the architecture of large RNAs and their dynamics, to new insights into how nucleic acids are recognized by proteins and small molecules, and the new groundbreaking technology, CRISPR-Cas, which is transforming biology and medicine. This issue reports two different approaches for recognizing single stranded nucleic acids. Ramos and coworkers report recent structural findings on how hnRNP K homology domain (KH) recognize single-stranded RNA. While most KH domains were found to recognize C-containing or A-containing RNA, the Ramos group could show with one KH-domain of KSRP that Grich sequence could also be sequence-specifically bound to such fold when widening the binding groove of the domain. They additionally review recent findings on extended KH domain and in particular on RNA recognition and dimerization of STAR domains. Single-stranded DNA binding is also reviewed by Campagne and coworkers in the context of sigma factor DNA recognition. This review presents recent structural findings on how specific sigma factors can target a subset of promotors independently and using a different recognition mechanism than the housekeeping sigma factors. The review also touches upon the regulation of transcription and how a two-component system can mimic sigma factor to activate transcription. Structure determination of large non-coding RNA presents a considerable challenge because they can be flexible and difficult to crystallize for X-ray crystallography or press the size-limits of NMR spectroscopy. Wang and colleagues review how small angle X-ray scattering (SAXS) is making into possible to transform an RNA secondary structure, which is increasingly accessible by ‘chemical probing’ technologies, into a 3D conformation Current Opinion in Structural Biology 2015, 30:1–2
Please cite this article in press as: Allain FH-T, Al-Hashimi HM: Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries, Curr Opin Struct Biol (2015), http://dx.doi.org/10.1016/j.sbi.2015.03.006
COSTBI-1331; NO. OF PAGES 2
2 Nucleic acids
outlining the overall RNA fold. Thus, by combining topological constraints encoded by an RNA secondary structure, with the powerful information regarding overall shape obtained by SAXS, it is now increasingly possible to determine the tertiary folds of large non-coding RNAs. These developments help to narrow the current divide between RNA secondary and tertiary structure. Nucleic acids are highly flexible and their structures often have to contort in specific ways when carrying out their biological functions. Zhang and colleagues review a growing repertoire of NMR techniques that are making it possible to characterize dynamic excursions away from energetically stable ‘ground states’ of RNA towards higher energy, low populated, and short-lived ‘excited states’ that are difficult to characterize by conventional methods. These studies suggest that most RNAs do not adopt a single secondary structure, but rather, are in constant rapid motion with related secondary structures. They review how these rapid RNA switches can be integrated into a wide variety of circuits to achieve different regulatory functions. Riboswitches are an example par excellence of non-coding RNAs that use shape-shifting to carry out regulatory functions in gene expression regulation. The working model has been based on aptamer domains switching between a ligand-free or ligand-bound conformation. Schwalbe and coworkers review recent studies that are challenging this simple two-state model to reveal higher order complexities. These studies suggest that conformational heterogeneity, particularly in the ligand free RNA, provide a basis for fine-tuning gene regulation and for achieving more sensitivity to multiple environmental inputs. Achieving a truly predictive understanding of how RNA carries out its biological function ultimately requires
Current Opinion in Structural Biology 2015, 30:1–2
models that can predict RNA folding behavior based on first principles. Herschlag and coworkers review an approach that seeks to deconstruct RNA into basic building components, such as helix–junction–helix and tertiary motifs, and to obtain unprecedented insights into the structural, dynamic and energetic properties of these components by applying new biophysical methods that make it possible to describe the structure of such components in terms of statistical ensembles. These advances provide a basis for reconstituting RNA folding from first principles, and to reveal hitherto unknown forces and interactions that may play important roles in RNA folding and function. A major breakthrough in recent year in both fundamental research and biotechnology is certainly the discovery of the CRISPR-Cas bacterial defense system and its application for genome editing. Doudna and coworkers superbly review the recent structural findings on the different types of CRISPR-Cas. The review illustrates the huge diversity of organization, the large conformational changes and the interplay between double-stranded and single-stranded nucleic acid recognition of the different types of CRISPR-Cas. The importance of the structural knowledge for the genome editing is of course touched upon. Non-coding RNAs can potentially revolutionize the scope of drug discovery by providing new targets for treating human diseases for which there are presently no suitable druggable protein targets. Efforts to target RNAs using RNA-based therapeutics have been road blocked by severe delivery limitations. Small molecules provide an alternative approach for targeting RNA that has not been fully explored. Varani and coworkers review recent progress in the development and application of methods for targeting a wide range of disease-relevant non-coding RNAs with small molecules.
www.sciencedirect.com
Please cite this article in press as: Allain FH-T, Al-Hashimi HM: Editorial overview: Nucleic acids and their protein complexes: Progress in nucleic acid structural biology: new technologies and discoveries, Curr Opin Struct Biol (2015), http://dx.doi.org/10.1016/j.sbi.2015.03.006