Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS

Elam, Jennifer Stine; Taylor, Alexander B.; Strange, R.W.; Antonyuk, S.V.; Doucette, P.A.; Rodríguez, Jorge A.; Hasnain, S.S.; Hayward, Lawrence J.; Valentine, Joan Selverstone; Yeates, Todd O.; Hart, P. John

doi:10.1038/nsb935

Cited by 305 publications

(324 citation statements)

References 54 publications

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“…8(a), a lateral interaction is formed involving a network of four hydrogen bonds between the outside strands of antiparallel -sheets on neighboring molecules. This lateral interaction has pseudotwofold symmetry similar to that observed in other types of amyloid-fibril models (Serag et al, 2002;Elam et al, 2003). Residues 11-13 in both molecules contribute to this interaction.…”

Section: Discussionsupporting

confidence: 49%

Bence Jones KWR protein structures determined by X-ray crystallography

Makino

Henschen-Edman

Larson

et al. 2007

Acta Crystallogr D Biol Cryst

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A Bence Jones protein isolated in the early 1960s from a patient (initials KWR) suffering from plasma-cell dyscrasia was crystallized and its structure was analyzed in four different unit cells by X-ray diffraction. The final models of the molecule in all crystal forms were virtually the same, although the elbow angles relating the constant and variable domains of the Bence Jones dimers varied over a range of 10 . The tetragonal form had an R factor of 22.6% and an R free of 28.3% at 2.2 Å resolution. Phosphate or sulfate ions (depending on the crystallization conditions) were found in the antigen-combining sites in all crystals, as well as an unidentified ligand tightly bound in the hydrophobic 'deep pocket' beneath the antigen-binding site. The ligand was treated as a phenol molecule. Two trigonal crystal forms were among those solved. One was grown at pH 4.0 and the other was only obtained after sitting for more than eight months at room temperature. The latter crystal was composed of molecules that were degraded in their constant domains. Both low pH and proteolytic degradation of constant domains are known to promote the polymerization of some Bence Jones proteins into amyloid fibrils. Indeed, in both trigonal crystal forms the molecules are organized with pseudo-hexagonal symmetry about the unique crystallographic axes in a manner suggestive of such fibrils. The arrangement of Bence Jones dimers is also consistent with other observations regarding Bence Jones amyloid-fibril structure and current models. PDB References: Bence Jones KWR protein, P3 1 21, 2omb, r2ombsf; P3 2 21, 2old, r2oldsf; P4 3 2 1 2, 2omn, r2omnsf.

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Section: Discussionsupporting

confidence: 49%

Bence Jones KWR protein structures determined by X-ray crystallography

Makino

Henschen-Edman

Larson

et al. 2007

Acta Crystallogr D Biol Cryst

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“…Although the solution-scattering data do not provide evidence that the mutant enzymes oligomerize at the solution concentrations and buffer conditions used in our in vitro experiments, it is possible that an oxidatively damaged and͞or metal-deficient species is responsible for oligomerization or aggregation in vivo (40)(41)(42). In fact, recent structures of metal-deficient S134N and H46R FALS mutants (35) showed that these mutant SOD enzymes formed amyloid-like fibrils in the crystals. It remains to be determined whether the metallated A4V and I113T SOD1 mutants examined here share a common mechanism of cellular **Scattering data for BSOD at 4 and 50°C are indistinguishable.…”

Section: Resultsmentioning

confidence: 76%

“…The observation of this packing motif in all of these structures of metallated human SOD1, in several space groups and significantly different crystallization conditions, suggests that it is a strongly preferred means of interaction between metal-loaded SOD1 molecules. Notably, the crystal structures of apo wild-type (14) and several metal-deficient mutants of SOD1 showed distinctly different modes of crystal packing in which so-called linear, zig-zag, and helical fibril-like arrangements were observed (35). This observation was proposed to be the result of a loss of order in the electrostatic and Zn loops in the metaldeficient SOD1 proteins, leading to the accessibility of a gain-of interaction interface, due to the deprotection of edge strands in the ␤-barrel.…”

Section: Resultsmentioning

confidence: 99%

Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants

Hough

Grossmann

Antonyuk

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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204

208

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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.human superoxide dismutase ͉ crystal structure ͉ x-ray solution scattering ͉ neurodegenerative disease

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“…Crystallographic studies of the metal-deficient form of the ALSmutant SOD1 (H46R and S134N) provide insights into the oligomerization and possible oxidation of the protein (35); ALS mutations induce conformational changes in SOD1 that facilitate new noncovalent nonnative protein-protein interactions and lead to the formation of amyloid-like filamentous assemblies. X-ray solution scattering data on SOD1 mutant protein (A4V and I113T) also have implied a strikingly different monomer-monomer interface compared with the WT protein (14).…”

Section: Discussionmentioning

confidence: 99%

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

Furukawa¹,

Deng

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

195

186

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Point mutations in Cu, Zn-superoxide dismutase (SOD1) cause a familial form of the neurodegenerative disease amyotrophic lateral sclerosis (ALS). Aggregates of mutant SOD1 proteins are observed in histopathology and are invoked in several proposed mechanisms for motor neuronal death; however, the significant stability and activity of the mature mutant proteins are not readily explained in such models. Recent biochemical studies suggest that it is the immature disulfide-reduced forms of the familial ALS mutant SOD1 proteins that play a critical role; these forms tend to misfold, oligomerize, and readily undergo incorrect disulfide formation upon mild oxidative stress in vitro. Here we provide physiological support for this mechanism of aggregate formation and show that a significant fraction of the insoluble SOD1 aggregates in spinal cord of the ALS-model transgenic mice contain multimers cross-linked via intermolecular disulfide bonds. These insoluble disulfide-linked SOD1 multimers are found only in the spinal cord of symptomatic transgenic animals, are not observed in unafflicted tissue such as brain cortex and liver, and can incorporate WT SOD1 protein. The findings provide a biochemical basis for a pathological hallmark of this disease; namely, incorrect disulfide cross-linking of the immature, misfolded mutant proteins leads to insoluble aggregates. disulfide bond ͉ protein aggregation ͉ oxidative stress ͉ neurodegnerative disease A myotrophic lateral sclerosis (ALS) is one of the most common adult-onset neurodegenerative diseases, and, in 1993, several mutations in the Cu, Zn-superoxide dismutase (SOD1) gene were identified as a cause of a subset of familial ALS (fALS) (1, 2). Since that time, Ͼ100 types of SOD1 mutations have been linked with fALS; however, its molecular mechanism remains unresolved. SOD1, which is a homodimer with a copper and zinc ion in each subunit, functions as an antioxidant enzyme by converting superoxide radical to oxygen and hydrogen peroxide (3). Some of the SOD1 mutant proteins have comparable levels of dismutase activity, and the SOD1-knockout mouse does not develop ALS-like motor neuron symptoms (4), leading to the idea that SOD1-mediated toxicity in fALS is due to a new activity acquired by mutations in the SOD1 gene. One of the proposed toxic functions in the SOD1 mutant proteins is an aberrant copper chemistry. A subset of ALS mutations in SOD1 can lead to catalytic nitration of tyrosine residues and peroxide or superoxide production at the copper site (5); however, the copper-toxicity model is difficult to reconcile with the fact that ALS symptoms still are observed in the transgenic mouse expressing SOD1 proteins in which all four copper ligands are mutated (6). Although some copper chelators can reduce the toxicity of mutant proteins in transgenic ALS model mice (7), a role for aberrant copper chemistry in the disease has not been widely addressed.Another hypothesis for a gain of toxic function is that the mutations in SOD1 facilitate protein aggregation (8). An enzyma...

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Amyloid-like filaments and water-filled nanotubes formed by SOD1 mutant proteins linked to familial ALS

Cited by 305 publications

References 54 publications

Bence Jones KWR protein structures determined by X-ray crystallography

Bence Jones KWR protein structures determined by X-ray crystallography

Dimer destabilization in superoxide dismutase may result in disease-causing properties: Structures of motor neuron disease mutants

Disulfide cross-linked protein represents a significant fraction of ALS-associated Cu, Zn-superoxide dismutase aggregates in spinal cords of model mice

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