Structural insights into IMP2 dimerization and RNA binding

Zorc, S.; Munoz-Tello, P.; O'Leary, T.; Yu, X.; Nag, M.; Hansel-Harris, A.; Forli, S.; Griffin, P. R.; Kojetin, D. J.; Roy, R. N.; Janiszewska, M.

doi:10.1101/2024.02.16.580656

bioRxiv · 10.1101/2024.02.16.580656

Structural insights into IMP2 dimerization and RNA binding

Zorc, S.·Munoz-Tello, P.·O'Leary, T.·Yu, X.·Nag, M.·Hansel-Harris, A.·Forli, S.·Griffin, P. R.·Kojetin, D. J.·Roy, R. N.·Janiszewska, M.

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Abstract

IGF2BP2 (IMP2) is an RNA-binding protein that contributes to cancer tumorigenesis and metabolic disorders. Structural studies focused on individual IMP2 domains have provided important mechanistic insights into IMP2 function; however, structural information on full-length IMP2 is lacking but necessary to understand how to target IMP2 activity in drug discovery. In this study, we investigated the behavior of full-length IMP2 and the influence of RNA binding using biophysical and structural methods including mass photometry, hydrogen-deuterium exchange coupled to mass spectrometry (HDX-MS), and small angle x-ray scattering (SAXS). We found that full-length IMP2 forms multiple oligomeric states but predominantly adopts a dimeric conformation. Molecular models derived from SAXS data suggest the dimer is formed in a head-to-tail orientation by the KH34 and RRM1 domains. Upon RNA binding, IMP2 forms a pseudo-symmetric dimer different from its apo/RNA-free state, with the KH12 domains of each IMP2 molecule forming the dimer interface. We also found that the formation of IMP2 oligomeric species, which includes dimers and higher-order oligomers, is sensitive to ionic strength and RNA binding. Our findings provide the first insight into the structural properties of full-length IMP2, which may lead to novel opportunities for disrupting its function with more effective IMP2 inhibitors.

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Zorc, S., Munoz-Tello, P., O'Leary, T., Yu, X., Nag, M., Hansel-Harris, A., Forli, S., Griffin, P. R., Kojetin, D. J., Roy, R. N., Janiszewska, M.. 2024-02-18. Structural insights into IMP2 dimerization and RNA binding. https://doi.org/10.1101/2024.02.16.580656

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