Copper reduction by copper binding proteins and its relation to neurodegenerative diseases.
Increasing evidence supports an important role for metals in neurobiology. In fact, copper binding proteins that form bioinorganic complexes are able to display oxidant or anti-oxidant properties, which would impact on neuronal function or in the triggering of neurodegenerative process. Two proteins related to neurodegenerative diseases have been described as copper binding proteins: the amyloid precursor protein (APP), a protein related to Alzheimer's disease, and the Prion protein (PrP), related to Creutzfeldt-Jakob disease. We used different synthetic peptides from APP and PrP sequences in order to evaluate the ability to reduce copper. We observed that APP(135-156), amyloid-beta-peptide (A beta(1-40)), and PrP(59-91) all have copper reducing ability, with the APP(135-156) peptide being more potent than the other fragments. Moreover, we identify His, Cys and Trp residues as key amino acids involved in the copper reduction of A beta, APP and PrP, respectively. We postulated, that in a cellular context, the interaction of these proteins with copper could be necessary to reduce copper on plasma membrane, possibly presenting Cu(I) to the copper transporter, driving the delivery of this metal to antioxidant enzymes. Moreover, protein-metal complexes could be the catalytic centers for the formation of reactive oxygen species involved in the oxidative damage present both in Alzheimer's and Prion disease.
Opazo
Carlos
C
Centro de Regulación Celular y Patología, MIFAB, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile.
Barría
María Inés
MI
Ruiz
Francisca H
FH
Inestrosa
Nibaldo C
NC
D000544:Alzheimer Disease / Q000378:metabolism; D000595:Amino Acid Sequence; D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000737:chemistry / Q000378:metabolism*; D003300:Copper / Q000378:metabolism*; D007562:Creutzfeldt-Jakob Syndrome / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D019636:Neurodegenerative Diseases / Q000378:metabolism*; D010084:Oxidation-Reduction; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry; D011328:Prions / Q000737:chemistry / Q000378:metabolism*; D015032:Zinc / Q000494:pharmacology
D016564:Amyloid beta-Protein Precursor; D002352:Carrier Proteins; D010446:Peptide Fragments; D011328:Prions; C023548:copper-binding protein; D003300:Copper; D015032:Zinc