Structural basis underlying CAC RNA recognition by the RRM domain of dimeric RNA-binding protein RBPMS

Teplova, Marianna; Farazi, Thalia A.; Tuschl, Thomas; Patel, Dinshaw J.

doi:10.1017/S0033583515000207

Structural basis underlying CAC RNA recognition by the RRM domain of dimeric RNA-binding protein RBPMS

Journal Article · Tue Sep 08 04:00:00 EDT 2015 · Quarterly Reviews of Biophysics

DOI:https://doi.org/10.1017/S0033583515000207· OSTI ID:1430282

Teplova, Marianna ^[1]; Farazi, Thalia A. ^[2]; Tuschl, Thomas ^[2]; Patel, Dinshaw J. ^[1]

Memorial Sloan-Kettering Cancer Center, New York, NY (United States)
The Rockefeller Univ., New York, NY (United States)

RNA-binding protein with multiple splicing (designated RBPMS) is a higher vertebrate mRNA-binding protein containing a single RNA recognition motif (RRM). RBPMS has been shown to be involved in mRNA transport, localization and stability, with key roles in axon guidance, smooth muscle plasticity, as well as regulation of cancer cell proliferation and migration. We report on structure-function studies of the RRM domain of RBPMS bound to a CAC-containing single-stranded RNA. These results provide insights into potential topologies of complexes formed by the RBPMS RRM domain and the tandem CAC repeat binding sites as detected by photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation. These studies establish that the RRM domain of RBPMS forms a symmetrical dimer in the free state, with each monomer binding sequence-specifically to all three nucleotides of a CAC segment in the RNA bound state. Structure-guided mutations within the dimerization and RNA-binding interfaces of RBPMS RRM on RNA complex formation resulted in both disruption of dimerization and a decrease in RNA-binding affinity as observed by size exclusion chromatography and isothermal titration calorimetry. Here, as anticipated from biochemical binding studies, over-expression of dimerization or RNA-binding mutants of Flag-HA-tagged RBPMS were no longer able to track with stress granules in HEK293 cells, thereby documenting the deleterious effects of such mutations in vivo.

View Accepted Manuscript (DOE)

Research Organization:: Argonne National Laboratory (ANL), Argonne, IL (United States)

Sponsoring Organization:: NIH; RU CCTS

OSTI ID:: 1430282

Journal Information:: Quarterly Reviews of Biophysics, Journal Name: Quarterly Reviews of Biophysics Journal Issue: 2016 Vol. 49; ISSN 0033-5835

Publisher:: Cambridge University PressCopyright Statement

Country of Publication:: United States

Language:: ENGLISH

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Molecular basis for AU-rich element recognition and dimerization by the HuR C-terminal RRM Ripin, Nina; Boudet, Julien; Duszczyk, Malgorzata M. Proceedings of the National Academy of Sciences, Vol. 116, Issue 8 https://doi.org/10.1073/pnas.1808696116	journal	February 2019
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Identification of RBPMS as a smooth muscle master splicing regulator via proximity of its gene with super-enhancers Nakagaki-Silva, Erick E.; Gooding, Clare; Llorian, Miriam eLife https://doi.org/10.1101/563304	journal	March 2019
Expanding the spectrum of pediatric NTRK ‐rearranged fibroblastic tumors to the central nervous system: A case report with RBPMS‐NTRK3 fusion Torre, Matthew; Jessop, Nicholas; Hornick, Jason L. Neuropathology, Vol. 38, Issue 6 https://doi.org/10.1111/neup.12513	journal	September 2018
rbpms2 functions in Balbiani body architecture and ovary fate Kaufman, Odelya H.; Lee, KathyAnn; Martin, Manon PLOS Genetics, Vol. 14, Issue 7 https://doi.org/10.1371/journal.pgen.1007489	journal	July 2018
Identification of RBPMS as a mammalian smooth muscle master splicing regulator via proximity of its gene with super-enhancers. Nakagaki-Silva, Erick E.; Gooding, Clare; Llorian, Miriam Apollo - University of Cambridge Repository https://doi.org/10.17863/cam.41008	text	January 2019
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59 BASIC BIOLOGICAL SCIENCES
RNA recognition element
RNA recognition motif
The RNA-binding protein with multiple splicing
photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation

Structural basis underlying CAC RNA recognition by the RRM domain of dimeric RNA-binding protein RBPMS

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