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Exposure of Solvent-Inaccessible Regions in the Amyloidogenic Protein Human SOD1 Determined by Hydroxyl Radical Footprinting.
Sheng, Yuewei; Capri, Joseph; Waring, Alan; Valentine, Joan Selverstone; Whitelegge, Julian.
Afiliación
  • Sheng Y; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
  • Capri J; The Pasarow Mass Spectrometry Laboratory, University of California, Los Angeles, CA, USA.
  • Waring A; Department of Medicine, University of California, Los Angeles, CA, USA.
  • Valentine JS; Department of Chemistry and Biochemistry, University of California, Los Angeles, CA, USA.
  • Whitelegge J; The Pasarow Mass Spectrometry Laboratory, University of California, Los Angeles, CA, USA. jpw@chem.ucla.edu.
J Am Soc Mass Spectrom ; 30(2): 218-226, 2019 Feb.
Article en En | MEDLINE | ID: mdl-30328005
Solvent-accessibility change plays a critical role in protein misfolding and aggregation, the culprit for several neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS). Mass spectrometry-based hydroxyl radical (·OH) protein footprinting has evolved as a powerful and fast tool in elucidating protein solvent accessibility. In this work, we used fast photochemical oxidation of protein (FPOP) hydroxyl radical (·OH) footprinting to investigate solvent accessibility in human copper-zinc superoxide dismutase (SOD1), misfolded or aggregated forms of which underlie a portion of ALS cases. ·OH-mediated modifications to 56 residues were detected with locations largely as predicted based on X-ray crystallography data, while the interior of SOD1 ß-barrel is hydrophobic and solvent-inaccessible and thus protected from modification. There were, however, two notable exceptions-two closely located residues inside the ß-barrel, predicted to have minimal or no solvent accessibility, that were found modified by FPOP (Phe20 and Ile112). Molecular dynamics (MD) simulations were consistent with differential access of peroxide versus quencher to SOD1's interior complicating surface accessibility considerations. Modification of these two residues could potentially be explained either by local motions of the ß-barrel that increased peroxide/solvent accessibility to the interior or by oxidative events within the interior that might include long-distance radical transfer to buried sites. Overall, comparison of modification patterns for the metal-free apoprotein versus zinc-bound forms demonstrated that binding of zinc protected the electrostatic loop and organized the copper-binding site. Our study highlights SOD1 hydrophobic groups that may contribute to early events in aggregation and discusses caveats to surface accessibility conclusions. Graphical Abstract.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solventes / Radical Hidroxilo / Huella de Proteína / Superóxido Dismutasa-1 Idioma: En Revista: J Am Soc Mass Spectrom Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Solventes / Radical Hidroxilo / Huella de Proteína / Superóxido Dismutasa-1 Idioma: En Revista: J Am Soc Mass Spectrom Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Estados Unidos