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Insights into the full-length SRPK2 structure and its hydrodynamic behavior
Éverton de Almeida Alves Barbosa1, Thiago Vargas Seraphim2, César Augusto Gandin3
1Departamento de Bioquímica e Biologia Molecular, Universidade Federal de Viçosa, Viçosa, MG, Brazil.
Abstract:
The serine/arginine-rich protein kinase 2 (SRPK2) has been reported as upregulated in several cancer types, with roles in hallmarks such as cell migration, growth, and apoptosis. These findings have indicated that SRPK2 is a promising emerging target in drug discovery initiatives. Although high-resolution models are available for SRPK2 (PDB 2X7G), they have been obtained with a heavily truncated recombinant protein version (~50% of the primary structure), due to the presence of long intrinsically unstructured regions. In the present work, we sought to characterize the structure of a full-length recombinant version of SRPK2 in solution. Low-resolution Small-Angle X-ray Scattering data were obtained for both versions of SRPK2. The truncated ΔNΔS-SRPK2 presented a propensity to dimerize at higher concentrations whereas the full-length SRPK2 was mainly found as dimers. The hydrodynamic behavior of the full-length SRPK2 was further investigated by analytical size exclusion chromatography and sedimentation velocity analytical ultracentrifugation experiments. SRPK2 behaved as a monomer-dimer equilibrium and both forms have an elongated shape in solution, pointing to a stretched-to-closed tendency among the conformational plasticity observed. Taken together, these findings allowed us to define unique structural features of the SRPK2 within SRPK family, characterized by its flexible regions outside the bipartite kinase domain.
Insights
Serine/arginine-rich protein kinase 2 (SRPK2) is a cancer target. This study characterized full-length SRPK2 in solution, revealing unique flexible regions and an elongated shape, distinct from truncated versions.
Area of Science:
- Biochemistry
- Structural Biology
- Molecular Biology
Background:
- Serine/arginine-rich protein kinase 2 (SRPK2) is upregulated in various cancers, contributing to cell migration, growth, and apoptosis.
- SRPK2 is a promising drug discovery target, but high-resolution structures are limited to truncated forms.
- Intrinsically unstructured regions in SRPK2 hinder structural characterization of full-length protein.
Purpose of the Study:
- To characterize the solution structure of full-length recombinant SRPK2.
- To compare the structural properties of full-length SRPK2 with a truncated version.
- To define unique structural features of SRPK2 within the SRPK family.
Main Methods:
- Small-Angle X-ray Scattering (SAXS) for low-resolution structural data.
- Analytical Size Exclusion Chromatography (SEC) for hydrodynamic behavior.
- Sedimentation Velocity Analytical Ultracentrifugation (SV-AUC) for molecular weight and shape determination.
Main Results:
- Full-length SRPK2 exists mainly as dimers in solution, unlike the truncated version which showed dimerization propensity at higher concentrations.
- SRPK2 exhibits a monomer-dimer equilibrium in solution.
- Both monomeric and dimeric forms of SRPK2 possess an elongated shape, indicating conformational flexibility.
- Flexible regions outside the bipartite kinase domain contribute to SRPK2's unique structural characteristics.
Conclusions:
- Full-length SRPK2 displays distinct structural features compared to truncated variants, characterized by its elongated shape and conformational plasticity.
- The identified flexible regions are unique to SRPK2 within the SRPK family.
- Understanding SRPK2's solution structure provides insights for targeted drug development in cancer therapy.
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