Global Pairwise RNA Interaction Landscapes Reveal Core Features of Protein Recognition

Overview

Journal Nat Commun

Specialty Biology

Date 2018 Jun 30

PMID 29955037

Citations 21

Authors

Qin Zhou

Nikesh Kunder

Jose Alberto de la Paz

Alexandra E Lasley

Vandita D Bhat

Faruck Morcos

Zachary T Campbell

Affiliations

Soon will be listed here.

Abstract

RNA-protein interactions permeate biology. Transcription, translation, and splicing all hinge on the recognition of structured RNA elements by RNA-binding proteins. Models of RNA-protein interactions are generally limited to short linear motifs and structures because of the vast sequence sampling required to access longer elements. Here, we develop an integrated approach that calculates global pairwise interaction scores from in vitro selection and high-throughput sequencing. We examine four RNA-binding proteins of phage, viral, and human origin. Our approach reveals regulatory motifs, discriminates between regulated and non-regulated RNAs within their native genomic context, and correctly predicts the consequence of mutational events on binding activity. We design binding elements that improve binding activity in cells and infer mutational pathways that reveal permissive versus disruptive evolutionary trajectories between regulated motifs. These coupling landscapes are broadly applicable for the discovery and characterization of protein-RNA recognition at single nucleotide resolution.

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References

De Gregorio E, Preiss T, Hentze M . Translation driven by an eIF4G core domain in vivo. EMBO J. 1999; 18(17):4865-74. PMC: 1171558. DOI: 10.1093/emboj/18.17.4865. View

Kozak M . Regulation of translation via mRNA structure in prokaryotes and eukaryotes. Gene. 2005; 361:13-37. DOI: 10.1016/j.gene.2005.06.037. View

Ouyang Z, Snyder M, Chang H . SeqFold: genome-scale reconstruction of RNA secondary structure integrating high-throughput sequencing data. Genome Res. 2012; 23(2):377-87. PMC: 3561878. DOI: 10.1101/gr.138545.112. View

Gueudre T, Baldassi C, Zamparo M, Weigt M, Pagnani A . Simultaneous identification of specifically interacting paralogs and interprotein contacts by direct coupling analysis. Proc Natl Acad Sci U S A. 2016; 113(43):12186-12191. PMC: 5087065. DOI: 10.1073/pnas.1607570113. View

Muller-McNicoll M, Neugebauer K . How cells get the message: dynamic assembly and function of mRNA-protein complexes. Nat Rev Genet. 2013; 14(4):275-87. DOI: 10.1038/nrg3434. View

Cilley C, Williamson J . Analysis of bacteriophage N protein and peptide binding to boxB RNA using polyacrylamide gel coelectrophoresis (PACE). RNA. 1997; 3(1):57-67. PMC: 1369462. View

Smith C, Crotty S, Harada Y, Frankel A . Altering the context of an RNA bulge switches the binding specificities of two viral Tat proteins. Biochemistry. 1998; 37(30):10808-14. DOI: 10.1021/bi980382+. View

Guenther U, Yandek L, Niland C, Campbell F, Anderson D, Anderson V . Hidden specificity in an apparently nonspecific RNA-binding protein. Nature. 2013; 502(7471):385-8. PMC: 3800043. DOI: 10.1038/nature12543. View

Starr T, Thornton J . Epistasis in protein evolution. Protein Sci. 2016; 25(7):1204-18. PMC: 4918427. DOI: 10.1002/pro.2897. View

10.

Sengupta D, Zhang B, Kraemer B, Pochart P, Fields S, Wickens M . A three-hybrid system to detect RNA-protein interactions in vivo. Proc Natl Acad Sci U S A. 1996; 93(16):8496-501. PMC: 38700. DOI: 10.1073/pnas.93.16.8496. View

11.

de Leonardis E, Lutz B, Ratz S, Cocco S, Monasson R, Schug A . Direct-Coupling Analysis of nucleotide coevolution facilitates RNA secondary and tertiary structure prediction. Nucleic Acids Res. 2015; 43(21):10444-55. PMC: 4666395. DOI: 10.1093/nar/gkv932. View

12.

Morcos F, Schafer N, Cheng R, Onuchic J, Wolynes P . Coevolutionary information, protein folding landscapes, and the thermodynamics of natural selection. Proc Natl Acad Sci U S A. 2014; 111(34):12408-13. PMC: 4151759. DOI: 10.1073/pnas.1413575111. View

13.

Opperman L, Hook B, DeFino M, Bernstein D, Wickens M . A single spacer nucleotide determines the specificities of two mRNA regulatory proteins. Nat Struct Mol Biol. 2005; 12(11):945-51. DOI: 10.1038/nsmb1010. View

14.

Carlson C, Warren C, Hauschild K, Ozers M, Qadir N, Bhimsaria D . Specificity landscapes of DNA binding molecules elucidate biological function. Proc Natl Acad Sci U S A. 2010; 107(10):4544-9. PMC: 2842033. DOI: 10.1073/pnas.0914023107. View

15.

Tome J, Ozer A, Pagano J, Gheba D, Schroth G, Lis J . Comprehensive analysis of RNA-protein interactions by high-throughput sequencing-RNA affinity profiling. Nat Methods. 2014; 11(6):683-8. PMC: 4073888. DOI: 10.1038/nmeth.2970. View

16.

Cai Z, Gorin A, Frederick R, Ye X, Hu W, Majumdar A . Solution structure of P22 transcriptional antitermination N peptide-boxB RNA complex. Nat Struct Biol. 1998; 5(3):203-12. DOI: 10.1038/nsb0398-203. View

17.

Bernstein D, Hook B, Hajarnavis A, Opperman L, Wickens M . Binding specificity and mRNA targets of a C. elegans PUF protein, FBF-1. RNA. 2005; 11(4):447-58. PMC: 1370734. DOI: 10.1261/rna.7255805. View

18.

Buenrostro J, Araya C, Chircus L, Layton C, Chang H, Snyder M . Quantitative analysis of RNA-protein interactions on a massively parallel array reveals biophysical and evolutionary landscapes. Nat Biotechnol. 2014; 32(6):562-8. PMC: 4414031. DOI: 10.1038/nbt.2880. View

19.

Hopf T, Ingraham J, Poelwijk F, Scharfe C, Springer M, Sander C . Mutation effects predicted from sequence co-variation. Nat Biotechnol. 2017; 35(2):128-135. PMC: 5383098. DOI: 10.1038/nbt.3769. View

20.

Warf M, Berglund J . Role of RNA structure in regulating pre-mRNA splicing. Trends Biochem Sci. 2009; 35(3):169-78. PMC: 2834840. DOI: 10.1016/j.tibs.2009.10.004. View