TY - JOUR
T1 - Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS
AU - Elam, Jennifer Stine
AU - Taylor, Alexander B.
AU - Strange, Richard
AU - Antonyuk, Svetlana
AU - Doucette, Peter A.
AU - Rodriguez, Jorge A.
AU - Hasnain, S. Samar
AU - Hayward, Lawrence J.
AU - Valentine, Joan Selverstone
AU - Yeates, Todd O.
AU - Hart, P. John
N1 - Funding Information:
We thank L. Flaks, and J. Berendzen for support at beamline X8-C at the NSLS, Brookhaven National Laboratory; D. Cascio and M. Hough for their interest and valuable discussions; S. Holloway for assistance with the illustrations and our colleagues who have offered comments during the preparation of this manuscript. This work was supported by the National Institutes of Health (L.J.H., J.S.V. and P.J.H.), the Robert A. Welch Foundation (P.J.H.), the ALS Association (L.J.H., J.S.V and P.J.H.), the MND Association (S.S.H.) and a predoctoral fellowship from the Association for the Advancement of Aging Research (J.S.E.). Funding from CCLRC and resources at Daresbury are also gratefully acknowledged.
PY - 2003/6/1
Y1 - 2003/6/1
N2 - Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed. Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery. Here we show that metal-deficient, pathogenic SOD1 mutant proteins crystallize in three different crystal forms, all of which reveal higher-order assemblies of aligned β-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and β-barrel elements of neighboring mutant SOD1 molecules. In all cases, non-native conformational changes permit a gain of interaction between dimers that leads to higher-order arrays. Normal β-sheet-containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions. Loss of this protection through conformational rearrangement in the metaldeficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.
AB - Mutations in the SOD1 gene cause the autosomal dominant, neurodegenerative disorder familial amyotrophic lateral sclerosis (FALS). In spinal cord neurons of human FALS patients and in transgenic mice expressing these mutant proteins, aggregates containing FALS SOD1 are observed. Accumulation of SOD1 aggregates is believed to interfere with axonal transport, protein degradation and anti-apoptotic functions of the neuronal cellular machinery. Here we show that metal-deficient, pathogenic SOD1 mutant proteins crystallize in three different crystal forms, all of which reveal higher-order assemblies of aligned β-sheets. Amyloid-like filaments and water-filled nanotubes arise through extensive interactions between loop and β-barrel elements of neighboring mutant SOD1 molecules. In all cases, non-native conformational changes permit a gain of interaction between dimers that leads to higher-order arrays. Normal β-sheet-containing proteins avoid such self-association by preventing their edge strands from making intermolecular interactions. Loss of this protection through conformational rearrangement in the metaldeficient enzyme could be a toxic property common to mutants of SOD1 linked to FALS.
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U2 - 10.1038/nsb935
DO - 10.1038/nsb935
M3 - Article
C2 - 12754496
AN - SCOPUS:0038442784
SN - 1072-8368
VL - 10
SP - 461
EP - 467
JO - Nature Structural Biology
JF - Nature Structural Biology
IS - 6
ER -