Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.

Banci, L.; Boca, M.; Girotto, S.; Bertini, I.; Vieru, M.; Calderone, V.; Cantini, F.

doi:10.1073/pnas.0809845106

Journal Article

PHPPUBDB-20353

Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.

Banci, L. ; Bertini, I. ; Boca, M. ; Calderone, V. ; Cantini, F. ; Girotto, S. ; Vieru, M. ; DESY

2009
Academy Washington, DC

Proceedings of the National Academy of Sciences of the United States of America 106, 6980-6985 (2009) [10.1073/pnas.0809845106]

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Please use a persistent id in citations: doi:10.1073/pnas.0809845106

Abstract: The structural and dynamical properties of the metal-free form of WT human superoxide dismutase 1 (SOD1) and its familial amyotrophic lateral sclerosis (fALS)-related mutants, T54R and I113T, were characterized both in solution, through NMR, and in the crystal, through X-ray diffraction. We found that all 3 X-ray structures show significant structural disorder in 2 loop regions that are, at variance, well defined in the fully-metalated structures. Interestingly, the apo state crystallizes only at low temperatures, whereas all 3 proteins in the metalated form crystallize at any temperature, suggesting that crystallization selects one of the most stable conformations among the manifold adopted by the apo form in solution. Indeed, NMR experiments show that the protein in solution is highly disordered, sampling a large range of conformations. The large conformational variability of the apo state allows the free reduced cysteine Cys-6 to become highly solvent accessible in solution, whereas it is essentially buried in the metalated state and the crystal structures. Such solvent accessibility, together with that of Cys-111, accounts for the tendency to oligomerization of the metal-free state. The present results suggest that the investigation of the solution state coupled with that of the crystal state can provide major insights into SOD1 pathway toward oligomerization in relation to fALS.

Keyword(s): Apoproteins: chemistry (MeSH) ; Apoproteins: genetics (MeSH) ; Apoproteins: metabolism (MeSH) ; Crystallography, X-Ray (MeSH) ; Humans (MeSH) ; Models, Molecular (MeSH) ; Mutation: genetics (MeSH) ; Nuclear Magnetic Resonance, Biomolecular (MeSH) ; Protein Multimerization (MeSH) ; Protein Structure, Quaternary (MeSH) ; Protein Structure, Secondary (MeSH) ; Protein Structure, Tertiary (MeSH) ; Superoxide Dismutase: chemistry (MeSH) ; Superoxide Dismutase: genetics (MeSH) ; Superoxide Dismutase: metabolism (MeSH) ; Apoproteins ; superoxide dismutase 1 ; Superoxide Dismutase