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| Home > Documents in process > Structural Implications of Missense Point Mutations in Shwachman–Bodian–Diamond Syndrome Protein (SBDS): A Combined SAXS/MD Investigation |
| Home > Documents in process > Structural Implications of Missense Point Mutations in Shwachman–Bodian–Diamond Syndrome Protein (SBDS): A Combined SAXS/MD Investigation |
| Journal Article | PUBDB-2025-04010 |
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2025
ACS Publications
Washington, DC
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Please use a persistent id in citations: doi:10.1021/acsomega.5c04764
Abstract: Shwachman–Diamond syndrome (SDS) is a rare autosomal recessive disorder characterized by pleiotropic phenotypes, including pancreatic insufficiency, skeletal abnormalities, and bone marrow dysfunction. Notably, patients with SDS exhibit an increased risk of developing myelodysplastic syndrome and leukemia. In this study, we employed a combination of comparative molecular dynamics (MD) simulations and small-angle X-ray scattering (SAXS)-based analysis to investigate the Shwachman–Bodian–Diamond syndrome protein (SBDS). Specifically, we explored the molecular basis of the syndrome by examining the conformational dynamics of a set of missense mutants of SBDS in comparison to those of the wild-type (WT) protein. Our observations suggest that different mutations may impact (i) the interaction of SBDS with the ribosome, (ii) the binding of SBDS to Elongation Factor-Like 1 (EFL1), and (iii) the SBDS rearrangements coupled to EFL1 binding. Extensive MD simulations, with a total simulation time of 17 μs, revealed variations in the interdomain flexibility of SBDS, which are consistent with previously published affinity data and the new SAXS experimental data presented here. We propose a structural rationale behind the previously reported weak interaction of mutants I167T, R175W, and I212T with EFL1. Additionally, SAXS data indicate that R19Q, I167T, and R175W mutants exhibit altered relative abundances of SBDS conformational states in solution, further supporting our computational results. Overall, our integrated computational and experimental approach provides a comprehensive understanding of how specific mutations in SBDS alter its structural dynamics and binding interactions. These insights enhance our broader understanding of SBDS function and its role in ribosome biogenesis.
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