TY  - JOUR
AU  - Banci, L.
AU  - Bertini, I.
AU  - Boca, M.
AU  - Calderone, V.
AU  - Cantini, F.
AU  - Girotto, S.
AU  - Vieru, M.
AU  - DESY
TI  - Structural and dynamic aspects related to oligomerization of apo SOD1 and its mutants.
JO  - Proceedings of the National Academy of Sciences of the United States of America
VL  - 106
SN  - 1091-6490
CY  - Washington, DC
PB  - Academy
M1  - PHPPUBDB-20353
SP  - 6980-6985
PY  - 2009
AB  - 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.
KW  - Apoproteins: chemistry
KW  - Apoproteins: genetics
KW  - Apoproteins: metabolism
KW  - Crystallography, X-Ray
KW  - Humans
KW  - Models, Molecular
KW  - Mutation: genetics
KW  - Nuclear Magnetic Resonance, Biomolecular
KW  - Protein Multimerization
KW  - Protein Structure, Quaternary
KW  - Protein Structure, Secondary
KW  - Protein Structure, Tertiary
KW  - Superoxide Dismutase: chemistry
KW  - Superoxide Dismutase: genetics
KW  - Superoxide Dismutase: metabolism
KW  - Apoproteins (NLM Chemicals)
KW  - superoxide dismutase 1 (NLM Chemicals)
KW  - Superoxide Dismutase (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:19369197
C2  - pmc:PMC2678485
UR  - <Go to ISI:>//WOS:000265584500022
DO  - DOI:10.1073/pnas.0809845106
UR  - https://bib-pubdb1.desy.de/record/96611
ER  -