TY - JOUR
T1 - Structural and biophysical properties of metal-free pathogenic SOD1 mutants A4V and G93A
AU - Galaleldeen, Ahmad
AU - Strange, Richard W.
AU - Whitson, Lisa J.
AU - Antonyuk, Svetlana V.
AU - Narayana, Narendra
AU - Taylor, Alexander B.
AU - Schuermann, Jonathan P.
AU - Holloway, Stephen P.
AU - Hasnain, S. Samar
AU - Hart, P. John
N1 - Funding Information:
This work was supported by grants NIH-NINDS R01-NS39112 (P.J.H.), the Motor Neuron Disease Association, U.K. (S.S.H., R.W.S), and in part by NIH T32AG021890-03 (J.P.S.), the American Foundation for Aging Research (L.J.W.), the William and Ella Owens Medical Research Foundation and the Judith and Jean Pape Adams Charitable Foundation (A.G.). The U.K. group is grateful to BBSRC, MRC, EPSRC, NWDA and STFC for financial support and to STFC Daresbury Laboratory for provision of facilities and also thanks Peter A. Doucette and Joan S. Valentine for the gift of G93A SOD1. Support for the X-ray Crystallography Core Laboratory and the Center for Analytical Ultracentrifugation of Macromolecular Assemblie s by the UTHSCSA Executive Research Committee and the San Antonio Cancer Institute is also gratefully acknowledged.
PY - 2009/1
Y1 - 2009/1
N2 - Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper-zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here we report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins.
AB - Amyotrophic lateral sclerosis (ALS) is a fatal, progressive neurodegenerative disease characterized by the destruction of motor neurons in the spinal cord and brain. A subset of ALS cases are linked to dominant mutations in copper-zinc superoxide dismutase (SOD1). The pathogenic SOD1 variants A4V and G93A have been the foci of multiple studies aimed at understanding the molecular basis for SOD1-linked ALS. The A4V variant is responsible for the majority of familial ALS cases in North America, causing rapidly progressing paralysis once symptoms begin and the G93A SOD1 variant is overexpressed in often studied murine models of the disease. Here we report the three-dimensional structures of metal-free A4V and of metal-bound and metal-free G93A SOD1. In the metal-free structures, the metal-binding loop elements are observed to be severely disordered, suggesting that these variants may share mechanisms of aggregation proposed previously for other pathogenic SOD1 proteins.
KW - A4V and G93A
KW - Amyotrophic lateral sclerosis
KW - Leu Gehrig's disease
KW - Protein structure
KW - X-ray crystallography
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U2 - 10.1016/j.abb.2009.09.020
DO - 10.1016/j.abb.2009.09.020
M3 - Article
C2 - 19800308
AN - SCOPUS:70450286167
SN - 0003-9861
VL - 492
SP - 40
EP - 47
JO - Archives of Biochemistry and Biophysics
JF - Archives of Biochemistry and Biophysics
IS - 1-2
ER -