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Crystal Structures and RNA-binding Properties of the RNA Recognition Motifs of Heterogeneous Nuclear Ribonucleoprotein L
Abstract
Heterogeneous nuclear ribonucleoprotein L (hnRNP L) is an abundant RNA-binding protein implicated in many bioprocesses, including pre-mRNA processing, mRNA export of intronless genes, internal ribosomal entry site-mediated translation, and chromatin modification. It contains four RNA recognition motifs (RRMs) that bind with CA repeats or CA-rich elements. In this study, surface plasmon resonance spectroscopy assays revealed that all four RRM domains contribute to RNA binding. Furthermore, we elucidated the crystal structures of hnRNP L RRM1 and RRM34 at 2.0 and 1.8 Å, respectively. These RRMs all adopt the typical β1α1β2β3α2β4 topology, except for an unusual fifth β-strand in RRM3. RRM3 and RRM4 interact intimately with each other mainly through helical surfaces, leading the two β-sheets to face opposite directions. Structure-based mutations and surface plasmon resonance assay results suggested that the β-sheets of RRM1 and RRM34 are accessible for RNA binding. FRET-based gel shift assays (FRET-EMSA) and steady-state FRET assays, together with cross-linking and dynamic light scattering assays, demonstrated that hnRNP L RRM34 facilitates RNA looping when binding to two appropriately separated binding sites within the same target pre-mRNA. EMSA and isothermal titration calorimetry binding studies with in vivo target RNA suggested that hnRNP L-mediated RNA looping may occur in vivo . Our study provides a mechanistic explanation for the dual functions of hnRNP L in alternative splicing regulation as an activator or repressor. Background: hnRNP L is a multifunctional RNA-binding protein implicated in alternative splicing regulation, etc. Results: RRM1 and RRM34 of hnRNP L adopt nearly typical RRM topology and use β-sheets to bind RNA. Conclusion: hnRNP L RRM34 facilitates the target RNA with appropriate in-between distance to form a loop. Significance: RNA looping suggests a general mechanism for alternative splicing regulators possessing position-dependent dual roles.
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“The CACACA hexamer can be efficiently bound by heterogeneous nuclear ribonucleoproteins (hnRNPs), such as hnRNP L and hnRNP LL [76–78] but this binding may require more stringent spacing between the CA repeats.”
From Differential RNA packaging into small extracellular vesicles by neurons and astrocytes (2021) · cites this paper as [77]
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Metadata
- Authors
- Zhang, W., Zeng, F., Liu, Y., Zhao, Y., Lv, H., Niu, L., Teng, M., & Li, X.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2013-08
- Volume
- 288
- Issue
- 31
- Pages
- 22636-22649
- ISSN
- 0021-9258
- Cited by
- 40
- References
- 51
- Language
- en
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- creativecommons.org/licenses/by/4.0/ (vor, 2599 d)
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