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The potential of engineered eukaryotic RNA‐binding proteins as molecular tools and therapeutics

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Abstract Eukaroytic RNA‐binding proteins (RBPs) recognize and process RNAs through recognition of their sequence motifs via RNA‐binding domains (RBDs). RBPs usually consist of one or more RBDs and can include additional functional domains that modify or cleave RNA. Engineered RBPs have been used to answer basic biology questions, control gene expression, locate viral RNA in vivo, as well as many other tasks. Given the growing number of diseases associated with RNA and RBPs, engineered RBPs also have the potential to serve as therapeutics. This review provides an in depth description of recent advances in engineered RBPs and discusses opportunities and challenges in the field. This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Methods > RNA Nanotechnology RNA in Disease and Development > RNA in Disease
Modular nature of RNA‐binding proteins. RNA‐binding domains can act in an independent manner and when found in multiple copies can act cooperatively. Proteins are sized according to their amino acid lengths. Domains are represented in block structure
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Adding functional domains to the RBD. After the specific RBD for the engineered protein has been chosen, a functional domain can be added for functionality. RBD, RNA‐binding domain
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Building blocks of engineered RNA binding proteins. When designing RBPs as tools and therapeutics the tissue target, cell entry methods, and the localization of the RNA target also need to be considered. Stock images adapted from Servier Medical Art. RBPs, RNA‐binding proteins
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The recognition code for the PUF and PPR repeat domains. The specific amino acids at these positions in each repeat of the domain specify which RNA nucleotide is recognized. Domains can be built from this code to recognize specific sequences of RNA with caveats as discussed in the text. PUF, Pumillo family; PPR, pentatricopeptide
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Example RBDs with RNA substrates (shown in dark gray with block nucleotides). (a) The RRM of human RBFOX1 in complex with a 7‐mer oligo (UGCAUGU) which interacts through base stacking of aromatic residues and through ionic interactions. (b) DsRBD3 of human Staufen in complex with ARF1 RNA. Recognition through the specific shape of A‐form dsRNA and the 2' OH present on the RNA. (c) The KH1 domain of human MEX‐3C in complex with a 10‐mer RNA oligo. Recognition through hydrogen bonding and shape complementarity. (d) Transcription Factor IIIA zinc fingers 4–6 from Xenopus laevis bound to 5S rRNA (55‐mer). Recognition through base stacking of aromatic residues with RNA bases. (e) ZF1 and 2 of human MBNL1 in complex with RNA from Cardiac Troponin T, which interacts with the RNA via base stacking of aromatic residues and hydrogen bonding. (f) The human FMRP RGG motif in complex with G‐quadruplex RNA of sc1, which interacts with the RNA via the arginines present in these domains. (g) Human Pumilio 1 in complex with Puf5 RNA. This domain interacts with RNA via base stacking and hydrogen bonds. (h) Zea mays PPR10 in complex with an 18‐nt PSAJ RNA element. This domain interacts with RNA similar to PUF domains in that it utilizes hydrogen bonding and base stacking. The PDB entries are below the names in parentheses for all domains. All panels were made using Chimera (Pettersen et al., ). PF, Pumillo family; RBD, RNA‐binding domain; RRM, RNA recognition motif
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RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Methods > RNA Nanotechnology
RNA in Disease and Development > RNA in Disease

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