Responsive self-assembly of tectoRNAs with loop–receptor interactions from the tetrahydrofolate (THF) riboswitch

Mitchell, Charles; Polanco, Julio; DeWald, Laura E.; Kress, Dustin; Jaeger, Luc; Grabow, Wade W.

doi:10.1093/nar/gkz304

Cited by 11 publications

(7 citation statements)

References 65 publications

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“…Additionally, the predicted proteins from CCDC66 transcripts I and II were submitted to Pfam-sequence search ( https://pfam.xfam.org/ ) 19 for the prediction of known/potential domains and functional sequences. Additional alignments were carried out by Interpro ( https://www.ebi.ac.uk/interpro/ ) 69 , Motifscan ( https://myhits.isb-sib.ch/cgi-bin/motif_scan ), and Psipred ( http://bioinf.cs.ucl.ac.uk/psipred/ ) 69 . RNF123 variant impact predicted with Polyphen-2 ( http://genetics.bwh.harvard.edu/pph2/ ) 70 .…”

Section: Methodsmentioning

confidence: 99%

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

Murgiano

Becker

Spector

et al. 2020

Sci Rep

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Aberrant photoreceptor function or morphogenesis leads to blinding retinal degenerative diseases, the majority of which have a genetic aetiology. A variant in PRCD previously identified in Portuguese Water Dogs (PWDs) underlies prcd (progressive rod-cone degeneration), an autosomal recessive progressive retinal atrophy (PRA) with a late onset at 3–6 years of age or older. Herein, we have identified a new form of early-onset PRA (EOPRA) in the same breed. Pedigree analysis suggested an autosomal recessive inheritance. Four PWD full-siblings affected with EOPRA diagnosed at 2–3 years of age were genotyped (173,661 SNPs) along with 2 unaffected siblings, 2 unaffected parents, and 15 unrelated control PWDs. GWAS, linkage analysis and homozygosity mapping defined a 26-Mb candidate region in canine chromosome 20. Whole-genome sequencing in one affected dog and its obligatory carrier parents identified a 1 bp insertion (CFA20:g.33,717,704_33,717,705insT (CanFam3.1); c.2262_c.2263insA) in CCDC66 predicted to cause a frameshift and truncation (p.Val747SerfsTer8). Screening of an extended PWD population confirmed perfect co-segregation of this genetic variant with the disease. Western blot analysis of COS-1 cells transfected with recombinant mutant CCDC66 expression constructs showed the mutant transcript translated into a truncated protein. Furthermore, in vitro studies suggest that the mutant CCDC66 is mislocalized to the nucleus relative to wild type CCDC66. CCDC66 variants have been associated with inherited retinal degenerations (RDs) including canine and murine ciliopathies. As genetic variants affecting the primary cilium can cause ciliopathies in which RD may be either the sole clinical manifestation or part of a syndrome, our findings further support a role for CCDC66 in retinal function and viability, potentially through its ciliary function.

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Section: Methodsmentioning

confidence: 99%

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

Murgiano

Becker

Spector

et al. 2020

Sci Rep

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“…Both dimeric and monomeric assemblies are structurally similar ( Figure 4 c), but the latter captured two THF molecules rather than one in the former structure [ 158 ]. Both structures brought valuable insights into the function of THF riboswitch and led to the design of artificial homodimeric RNAs responsive to THF through a loop-receptor intermolecular interface [ 159 ]. Similar artificial constructs were previously formed through a GAAA tetraloop-receptor mediated homodimerization interface [ 151 , 152 , 160 ].…”

Section: Homodimerization Of Riboswitchesmentioning

confidence: 99%

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Bou‐Nader

Zhang

2020

Molecules

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In comparison with the pervasive use of protein dimers and multimers in all domains of life, functional RNA oligomers have so far rarely been observed in nature. Their diminished occurrence contrasts starkly with the robust intrinsic potential of RNA to multimerize through long-range base-pairing (“kissing”) interactions, self-annealing of palindromic or complementary sequences, and stable tertiary contact motifs, such as the GNRA tetraloop-receptors. To explore the general mechanics of RNA dimerization, we performed a meta-analysis of a collection of exemplary RNA homodimer structures consisting of viral genomic elements, ribozymes, riboswitches, etc., encompassing both functional and fortuitous dimers. Globally, we found that domain-swapped dimers and antiparallel, head-to-tail arrangements are predominant architectural themes. Locally, we observed that the same structural motifs, interfaces and forces that enable tertiary RNA folding also drive their higher-order assemblies. These feature prominently long-range kissing loops, pseudoknots, reciprocal base intercalations and A-minor interactions. We postulate that the scarcity of functional RNA multimers and limited diversity in multimerization motifs may reflect evolutionary constraints imposed by host antiviral immune surveillance and stress sensing. A deepening mechanistic understanding of RNA multimerization is expected to facilitate investigations into RNA and RNP assemblies, condensates, and granules and enable their potential therapeutical targeting.

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“…Understanding and realistic modeling of the intermolecular interactions important for RNA folding would provide a fundamental foundation for prediction. In addition, realistic modeling of interactions in nucleic acids would facilitate design of structures for applications in nanotechnology. − Many different interactions are involved, however, including stacking, hydrogen bonding, hydration, and electrostatics. Currently, in many calculations, these are approximated with classical force fields, but none have proven generally accurate for a wide range of experimental benchmarks. − …”

Section: Introductionmentioning

confidence: 99%

Nuclear Magnetic Resonance of Single-Stranded RNAs and DNAs of CAAU and UCAAUC as Benchmarks for Molecular Dynamics Simulations

Zhao

Kennedy

Berger

et al. 2020

J. Chem. Theory Comput.

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RNA and DNA are rapidly emerging as targets for therapeutics and as potential frameworks for nanotechnology. Accurate methods for predicting and designing structures and dynamics of nucleic acids would accelerate progress in these and other applications. Suitable approximations for modeling nucleic acids are being developed but require validation against disparate experimental observations. Here, nuclear magnetic resonance spectra for RNA and DNA single strands, CAAU and UCAAUC, are used as benchmarks to test molecular dynamics simulations with AMBER force fields OL3 and ROC-RNA for RNA and BSC1 for DNA. A detailed scheme for making comparisons is also presented. The results reflect recent progress in approximations and reveal remaining challenges.

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Responsive self-assembly of tectoRNAs with loop–receptor interactions from the tetrahydrofolate (THF) riboswitch

Cited by 11 publications

References 65 publications

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

CCDC66 frameshift variant associated with a new form of early-onset progressive retinal atrophy in Portuguese Water Dogs

Structural Insights into RNA Dimerization: Motifs, Interfaces and Functions

Nuclear Magnetic Resonance of Single-Stranded RNAs and DNAs of CAAU and UCAAUC as Benchmarks for Molecular Dynamics Simulations

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