Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain

Barnham, Kevin J.; McKinstry, William J.; Multhaup, Gerd; Galatis, Denise; Morton, Craig J.; Curtain, Cyril C.; Williamson, Nicholas A.; White, Anthony R.; Hinds, Mark G.; Norton, Raymond S.; Beyreuther, Konrad; Masters, Colin L.; Parker, Michael W.; Cappai, Roberto

doi:10.1074/jbc.m300629200

Cited by 272 publications

(262 citation statements)

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“…This conclusion is further supported by the observation that APLP2 knockout mice, like APP knockout mice, have increased brain Cu levels (31). APLP2 has a Cu-binding site that shares structural and functional homology with the APP Cu-binding ectodomain (7,8,10). Thus, deleterious effects of APP or APLP2 overexpression are likely due to an interference with Cu homeostasis and intracellular Cu trafficking (32).…”

Section: Discussionmentioning

confidence: 84%

“…More evidence that APP is directly or indirectly involved in intracellular Cu homeostasis is provided by the recently revealed structural homology of its CuBD to intracellular Cu chaperones (10) and the link to the Cu chaperone for SOD-1 (CCS). The neuronal adaptor protein, X11␣, interacts with the cytoplasmic domain of APP and CCS (33,34).…”

Section: Discussionmentioning

confidence: 99%

“…N-terminal CuBDs of APP family paralogs and orthologs were found to have antioxidant activities, whereas the recently evolved human APP exerts unique redox properties, suggesting an overall conservation in its function or activity (7)(8)(9). The underlying reaction, a reduction of Cu(II) to Cu(I), and the structural homology of the CuBD of APP to Cu chaperones suggests APP to function as a Cu(I)-binding neuronal metallochaperone (7,10). Potentially, APP-Cu(I) complexes may reduce hydrogen peroxide by forming an APP-Cu(II)-hydroxyl radical intermediate, or may modulate neurotoxicity and APP fragmentation (11)(12)(13) when Cu is allowed to accumulate beyond cellular needs.…”

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confidence: 99%

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Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Bayer

Schäfer

Simons

et al. 2003

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

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The Cu-binding ␤-amyloid precursor protein (APP), and the amyloid A␤ peptide have been proposed to play a role in physiological metal regulation. There is accumulating evidence of an unbalanced Cu homeostasis with a causative or diagnostic link to Alzheimer's disease. Whereas elevated Cu levels are observed in APP knockout mice, APP overexpression results in reduced Cu in transgenic mouse brain. Moreover, Cu induces a decrease in A␤ levels in APP-transfected cells in vitro. To investigate the influence of bioavailable Cu, transgenic APP23 mice received an oral treatment with Cu-supplemented sucrose-sweetened drinking water (1). Chronic APP overexpression per se reduced superoxide dismutase 1 activity in transgenic mouse brain, which could be restored to normal levels after Cu treatment (2). A significant increase of brain Cu indicated its bioavailability on Cu treatment in APP23 mice, whereas Cu levels remained unaffected in littermate controls (3). Cu treatment lowered endogenous CNS A␤ before a detectable reduction of amyloid plaques. Thus, APP23 mice reveal APP-induced alterations linked to Cu homeostasis, which can be reversed by addition of dietary Cu.

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Bayer

Schäfer

Simons

et al. 2003

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

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320

255

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“…Interestingly, APP has a selective, high-affinity Cu-binding site in the extracellular (ecto-) domain that is capable of reducing Cu(II) to Cu(I) (11), and a recent structural analysis of this domain has revealed some similarity to previously identified Cu chaperone proteins (12). In addition to the ectodomain Cu-binding site of APP, A␤ peptide also contains binding sites for Zn and Cu (13)(14)(15).…”

mentioning

confidence: 99%

In vivo reduction of amyloid-β by a mutant copper transporter

Phinney

Drisaldi

Schmidt

et al. 2003

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

204

153

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Cu ions have been suggested to enhance the assembly and pathogenic potential of the Alzheimer's disease amyloid-␤ (A␤) peptide. To explore this relationship in vivo, toxic-milk (tx J ) mice with a mutant ATPase7b transporter favoring elevated Cu levels were analyzed in combination with the transgenic (Tg) CRND8 amyloid precursor protein mice exhibiting robust A␤ deposition. Unexpectedly, TgCRND8 mice homozygous for the recessive tx J mutation examined at 6 months of age exhibited a reduced number of amyloid plaques and diminished plasma A␤ levels. In addition, homozygosity for tx J increased survival of young TgCRND8 mice and lowered endogenous CNS A␤ at times before detectable increases in Cu in the CNS. These data suggest that the beneficial effect of the tx J mutation on CNS A␤ burden may proceed by a previously undescribed mechanism, likely involving increased clearance of peripheral pools of A␤ peptide. A lzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by extracellular deposition of amyloid-␤ (A␤) as senile plaques and intracellular accumulation of hyperphosphorylated tau as neurofibrillary tangles (1). A␤ is generated by secretase-mediated endoproteolysis of the amyloid precursor protein (APP), and familial AD mutations skew APP processing to favor production of pro-amyloidogenic forms of the peptide or net A␤ production and thus drive disease pathogenesis. Although there is growing interest in defining pathogenic subvarieties of A␤ [e.g., secreted oligomeric assemblies such as A␤-derived diffusible ligands (2) and intracellular forms (3)], modulators of APP and A␤ biology in sporadic disease have remained more elusive. One area of particular interest concerns the role of transition metals.Cu and Zn ions are abundant in the normal brain (4-6), and direct measurements of metal levels have indicated altered homeostasis in AD (7-10). Interestingly, APP has a selective, high-affinity Cu-binding site in the extracellular (ecto-) domain that is capable of reducing Cu(II) to Cu(I) (11), and a recent structural analysis of this domain has revealed some similarity to previously identified Cu chaperone proteins (12). In addition to the ectodomain Cu-binding site of APP, A␤ peptide also contains binding sites for . A␤-metal interaction may drive both fibril formation and free radical production (13,(16)(17)(18), findings potentially relevant to AD pathogenesis in vivo, given that metal chelators can resolubilize A␤ aggregates from postmortem AD brain (19). On the other hand, studies of APP processing in cultured cells have revealed stimulation of the ␣-secretase pathway for APP processing by extracellular Cu ions (20). As this pathway cleaves the A␤ domain of APP into two fragments, it has a potential to be anti-amyloidogenic. Prompted by these divergent observations, we devised a genetic experiment to investigate how Cu might modulate A␤-dependent pathologies in vivo by using the transgenic (Tg) CRND8 line of TgAPP mice (21,22) in conjunction with a mutant allele of the CuATPase7b c...

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“…22 The fold of the dodecin subunit is also similar to the copper-binding domain (CuBD) of an Alzheimer's disease amyloid precursor protein (PDB: 1OWT), which is a neuronal regulator of copper homeostasis 23 with no apparent sequence identity (RMSD ¼ 7.66 Å over 59 C a atoms). Based on the hits from a similarity search, a structural motif containing a three-stranded twisted b-sheet and an amphipathic a-helix is present in several proteins with varying functions, and is not restricted to riboflavin-binding or calcium-binding dodecamers.…”

Section: Resultsmentioning

confidence: 99%

Crystal structure of calcium dodecin (Rv0379), from Mycobacterium tuberculosis with a unique calcium‐binding site

Arockiasamy¹,

Aggarwal²,

Savva³

et al. 2011

Protein Science

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In eukaryotes, calcium-binding proteins play a pivotal role in diverse cellular processes, and recent findings suggest similar roles for bacterial proteins at different stages in their life cycle. Here, we report the crystal structure of calcium dodecin, Rv0379, from Mycobacterium tuberculosis with a dodecameric oligomeric assembly and a unique calcium-binding motif. Structure and sequence analysis were used to identify orthologs of Rv0379 with different ligand-binding specificity.

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Structure of the Alzheimer's Disease Amyloid Precursor Protein Copper Binding Domain

Cited by 272 publications

References 46 publications

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

Dietary Cu stabilizes brain superoxide dismutase 1 activity and reduces amyloid Aβ production in APP23 transgenic mice

In vivo reduction of amyloid-β by a mutant copper transporter

Crystal structure of calcium dodecin (Rv0379), from Mycobacterium tuberculosis with a unique calcium‐binding site

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