TY - JOUR
T1 - Dimer destabilization in superoxide dismutase may result in disease-causing properties
T2 - Structures of motor neuron disease mutants
AU - Hough, Michael A.
AU - Grossmann, J. Günter
AU - Antonyuk, Svetlana V.
AU - Strange, Richard W.
AU - Doucette, Peter A.
AU - Rodriguez, Jorge A.
AU - Whitson, Lisa J.
AU - Hart, P. John
AU - Hayward, Lawrence J.
AU - Valentine, Joan Selverstone
AU - Hasnain, S. Samar
N1 - Copyright:
Copyright 2008 Elsevier B.V., All rights reserved.
PY - 2004/4/20
Y1 - 2004/4/20
N2 - More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile113Thr(I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.
AB - More than 90 point mutations in human CuZn superoxide dismutase lead to the development of familial amyotrophic lateral sclerosis, known also as motor neuron disease. A growing body of evidence suggests that a subset of mutations located close to the dimeric interface can lead to a major destabilization of the mutant enzymes. We have determined the crystal structures of the Ala4Val (A4V) and Ile113Thr(I113T) mutants to 1.9 and 1.6 Å, respectively. In the A4V structure, small changes at the dimer interface result in a substantial reorientation of the two monomers. This effect is also seen in the case of the I113T crystal structure, but to a smaller extent. X-ray solution scattering data show that in the solution state, both of the mutants undergo a more pronounced conformational change compared with wild-type superoxide dismutase (SOD) than that observed in the A4V crystal structure. Shape reconstructions from the x-ray scattering data illustrate the nature of this destabilization. Comparison of these scattering data with those for bovine CuZn SOD measured at different temperatures shows that an analogous change in the scattering profile occurs for the bovine enzyme in the temperature range of 70-80°C. These results demonstrate that the A4V and I113T mutants are substantially destabilized in comparison with wild-type SOD1, and it is possible that the pathogenic properties of this subset of familial amyotrophic lateral sclerosis mutants are at least in part due to this destabilization.
KW - Crystal structure
KW - Human superoxide dismutase
KW - Neurodegenerative disease
KW - X-ray solution scattering
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U2 - 10.1073/pnas.0305143101
DO - 10.1073/pnas.0305143101
M3 - Article
C2 - 15056757
AN - SCOPUS:11144357460
VL - 101
SP - 5976
EP - 5981
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 16
ER -