Structural insights into IMP2 dimerization and RNA binding

ABSTRACT: IGF2BP2 (IMP2) is an RNA binding protein contributing to tumorigenesis across various cancers as well as to metabolic disorders. With the growing interest in drug discovery efforts targeting IMP2, an understanding of its structural properties and biological behavior are needed. Thus far, only partial structural information was available based on selected domains purification. In this study we used a combination of mass photometry, Hydrogen-Deuterium exchange-mass spectrometry, small angle X-ray scattering, and additional biophysical experiments to investigate the behavior of full-length IMP2 protein in presence or absence or RNA. We found that full-length IMP2 forms multiple oligomeric states and predominantly adopts a dimer conformation. Interestingly, the dimer is formed in a head-to-tail orientation by KH34 and RRM1 domains. In the presence of a known IMP2-binding RNA target, we observed a pseudo-symmetric dimer much different from its RNA unbound state, with the KH12 domains of each IMP2 molecule forming the dimeric interface. Additionally, we observed that IMP2 oligomer species, including dimers and higher-order oligomers, are sensitive to environmental conditions such as ionic strength as well as the presence or absence of RNA. Our results provide the first insight into IMP2 homodimerization, which will provide novel opportunities for disrupting its function towards more effective IMP2 inhibitors.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Timothy O'Leary  

LAB HEAD: Patrick R. Griffin

PROVIDER: PXD049065 | Pride | 2026-05-25

REPOSITORIES: Pride