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@ARTICLE{Mattiotti:638192,
      author       = {Mattiotti, Giovanni and Nanna, Vittoria and Giulini, Marco
                      and Alberga, Domenico and Mangiatordi, Giuseppe Felice and
                      Sánchez-Puig, Nuria and Saviano, Michele and Tubiana, Luca
                      and Potestio, Raffaello and Lattanzi, Gianluca and Siliqi,
                      Dritan},
      title        = {{S}tructural {I}mplications of {M}issense {P}oint
                      {M}utations in {S}hwachman–{B}odian–{D}iamond {S}yndrome
                      {P}rotein ({SBDS}): {A} {C}ombined {SAXS}/{MD}
                      {I}nvestigation},
      journal      = {ACS omega},
      volume       = {10},
      number       = {31},
      issn         = {2470-1343},
      address      = {Washington, DC},
      publisher    = {ACS Publications},
      reportid     = {PUBDB-2025-04010},
      pages        = {35103 - 35118},
      year         = {2025},
      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.},
      cin          = {EMBL-User},
      ddc          = {660},
      cid          = {I:(DE-H253)EMBL-User-20120814},
      pnm          = {6G3 - PETRA III (DESY) (POF4-6G3)},
      pid          = {G:(DE-HGF)POF4-6G3},
      experiment   = {EXP:(DE-H253)P-P12-20150101},
      typ          = {PUB:(DE-HGF)16},
      doi          = {10.1021/acsomega.5c04764},
      url          = {https://bib-pubdb1.desy.de/record/638192},
}