Structural insights into IMP2 dimerization and RNA binding
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Abstract
IGF2BP2 (IMP2) is an RNA-binding protein that contributes to 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. 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.
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- Authors
- Zorc, S. A., Munoz-Tello, P., O’Leary, T., Yu, X., Karadi Giridhar, M. N., Hondros, A. D., Hansel-Harris, A., Forli, S., Griffin, P. R., Kojetin, D. J., Roy, R. N., & Janiszewska, M.
- Affiliations
- Scripps Research Institute (US)
- Vanderbilt University (US)
- The Herbert Wertheim UF Scripps Institute for Biomedical Innovation & Technology (US)
- Corresponding author
- Roy, Raktim N.
- Janiszewska, Michalina
- ORCID
- Venue
- Journal of Structural Biology
- Publisher
- Elsevier BV
- Published
- 2025-12
- Volume
- 217
- Issue
- 4
- Pages
- 108247
- ISSN
- 1047-8477 (ISSN-L)
- PMC
- PMC13160379
- OpenAlex
- W4414167621
- Cited by
- 5
- References
- 55
- Citations by year
- 2026: 3 · 2025: 1 · 2024: 1
- FWCI
- 1.20
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Structural Biology (publishedVersion, cc-by-nc-nd)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion)
- IUScholarWorks (Indiana University) (submittedVersion, cc-by-nc-nd)
- IUScholarWorks (Indiana University) (submittedVersion)
- PubMed Central (submittedVersion, cc-by-nc-nd)
- Funders
- Biological and Environmental Research (KP1605010, S10 OD012331)
- NIH (R01DK124870, R01AG070719, S10 OD012331)
- The Scripps Research Institute
- National Institute of General Medical Sciences (P30GM133893)
- Basic Energy Sciences (DE-SC0012704)
- U.S. Department of Energy
- Office of Science
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Physical Sciences › Materials Science › Materials Chemistry › Enzyme Structure and Function
- Keywords
- IGF2BP2, RNA-binding proteins, protein dimerization, oligomeric state, RRM1 domain, RNA binding, head-to-tail dimer, ionic strength sensitivity, full-length protein structure, carcinogenesis, therapeutic target
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