TY - JOUR
T1 - The structural basis for RNA selectivity by the IMP family of RNA-binding proteins
AU - Biswas, Jeetayu
AU - Patel, Vivek L.
AU - Bhaskar, Varun
AU - Chao, Jeffrey A.
AU - Singer, Robert H.
AU - Eliscovich, Carolina
N1 - Funding Information:
The authors would like to thank members of the Singer lab for their helpful discussions and comments. They would also like to thank members of the Einstein NMR core facility (Mark Girvin and Sean Cahill) for help with NMR acquisition and for supervision of the data analysis. CE and RHS were supported by NIH grant R01NS083085. JB was supported with funding from the MSTP Training Grant T32GM007288 and predoctoral fellowship F30CA214009. NMR spectra were acquired on a Bruker 600 MHz NMR instrument purchased using funds from NIH award 1S10OD016305 as well as a Bruker 80 MHz NMR instrument at the New York Structural Biology Center.
Publisher Copyright:
© 2019, The Author(s).
PY - 2019/12/1
Y1 - 2019/12/1
N2 - The IGF2 mRNA-binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved post-transcriptional regulators of RNA stability, localization and translation. They play important roles in cell migration, neural development, metabolism and cancer cell survival. The knockout phenotypes of individual IMP proteins suggest that each family member regulates a unique pool of RNAs, yet evidence and an underlying mechanism for this is lacking. Here, we combine systematic evolution of ligands by exponential enrichment (SELEX) and NMR spectroscopy to demonstrate that the major RNA-binding domains of the two most distantly related IMPs (ZBP1 and IMP2) bind to different consensus sequences and regulate targets consistent with their knockout phenotypes and roles in disease. We find that the targeting specificity of each IMP is determined by few amino acids in their variable loops. As variable loops often differ amongst KH domain paralogs, we hypothesize that this is a general mechanism for evolving specificity and regulation of the transcriptome.
AB - The IGF2 mRNA-binding proteins (ZBP1/IMP1, IMP2, IMP3) are highly conserved post-transcriptional regulators of RNA stability, localization and translation. They play important roles in cell migration, neural development, metabolism and cancer cell survival. The knockout phenotypes of individual IMP proteins suggest that each family member regulates a unique pool of RNAs, yet evidence and an underlying mechanism for this is lacking. Here, we combine systematic evolution of ligands by exponential enrichment (SELEX) and NMR spectroscopy to demonstrate that the major RNA-binding domains of the two most distantly related IMPs (ZBP1 and IMP2) bind to different consensus sequences and regulate targets consistent with their knockout phenotypes and roles in disease. We find that the targeting specificity of each IMP is determined by few amino acids in their variable loops. As variable loops often differ amongst KH domain paralogs, we hypothesize that this is a general mechanism for evolving specificity and regulation of the transcriptome.
UR - http://www.scopus.com/inward/record.url?scp=85072774341&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85072774341&partnerID=8YFLogxK
U2 - 10.1038/s41467-019-12193-7
DO - 10.1038/s41467-019-12193-7
M3 - Article
C2 - 31570709
AN - SCOPUS:85072774341
SN - 2041-1723
VL - 10
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 4440
ER -
