Abstract Details 121

Cu(I) Binding to the Fragment 106-115 of the Human Prion Protein
Abstract ID 121
Presenter Trinidad Arcos
Presentation Type Poster
Full Author List Munzarin Q., Marco M., Rafael G. A., Lina R. A., Claudio O. F., Britt H., Keith O. H., Alberto V., Edward I. S., Liliana Q.

Cinvestav, Stanford


Several neurodegenerative diseases, including transmissible spongiform encephalopathies diseases (TSEs), are characterized by the formation of proteic amyloid fibrils, where redox - active metals such as copper, iron and manganese also accumulate. [ 1 - 3 ] TSEs are associated to the conversion of the normal cellular form of prion protein (PrPC) into the infectious scrapie isoform (PrPSc). [ 1 ] PrPC has several binding sites for Cu at its N - terminal region. Human PrPC contains four Cu binding sites at residues 60 - 91, [ 4 ] while two Cu binding sites are located at His96 and His111. [ 5, 6 ] The His111 site (His111) is located in a region that is key for the conversion of PrPC to PrPSc; in fact, PrP(106 - 126) has similar properties to those of PrPSc, it is neurotoxic and generates hydrogen pero xide in the presence of Cu(II), reducing agents and oxygen. [ 7 ] Cu(II) binding to His111 is highly dependent on pH; two coordination modes (3N1O and 4N) are present at physiological pH. [ 8, 9 ]

In this work we study, both experimentally and theoretically, the coordination of Cu (I) to His111 in the human PrP(106 - 115) f ragment, evaluating the role of Met109 and Met112 in metal ion coordination . Our results indicate that the nature of the coordination shell of Cu(I) bound to PrP(106 - 115) is highly dependent on pH: at low pH it involves a NO2S coordination mode with the pa rticipation of Met109 and Met12, while at high pH a 2NOS coordination mode is favored, with a single Met residue bound to Cu(I). The participation of Met residues in the reduced form of Cu - PrP complexes is reflected in the reduction and re-oxidation proces ses. These results contribute to our understanding of the redox properties of this Cu binding site and provide insight into plausible mechanisms for copper transport by PrPC .



Funding Acknowledgement This research was funded by CONACYT grant #CB2009 - 128255, #193318 and #128369 to L. Q. and A. V., respectively and fellowships to T. A. , R. G. A. and L. R. A.