Comparative analysis of the human and chicken prion protein copper binding regions at pH 6.5.
Recent experimental evidence supports the hypothesis that prion proteins (PrPs) are involved in the Cu(II) metabolism. Moreover, the copper binding region has been implicated in transmissible spongiform encephalopathies, which are caused by the infectious isoform of prion proteins (PrP(Sc)). In contrast to mammalian PrP, avian prion proteins have a considerably different N-terminal copper binding region and, most interestingly, are not able to undergo the conversion process into an infectious isoform. Therefore, we applied x-ray absorption spectroscopy to analyze in detail the Cu(II) geometry of selected synthetic human PrP Cu(II) octapeptide complexes in comparison with the corresponding chicken PrP hexapeptide complexes at pH 6.5, which mimics the conditions in the endocytic compartments of neuronal cells. Our results revealed that structure and coordination of the human PrP copper binding sites are highly conserved in the pH 6.5-7.4 range, indicating that the reported pH dependence of copper binding to PrP becomes significant at lower pH values. Furthermore, the different chicken PrP hexarepeat motifs display homologous Cu(II) coordination at sub-stoichiometric copper concentrations. Regarding the fully cation-saturated prion proteins, however, a reduced copper coordination capability is supposed for the chicken prion protein based on the observation that chicken PrP is not able to form an intra-repeat Cu(II) binding site. These results provide new insights into the prion protein structure-function relationship and the conversion process of PrP.
Redecke
Lars
L
Center of Experimental Medicine, Institute of Biochemistry and Molecular Biology I, University Hospital Hamburg-Eppendorf, c/o Deutsches Elektronen Synchrotron (DESY), Hamburg, Germany.
Meyer-Klaucke
Wolfram
W
Koker
Mirjam
M
Clos
Joachim
J
Georgieva
Dessislava
D
Genov
Nicolay
N
Echner
Hartmut
H
Kalbacher
Hubert
H
Perbandt
Markus
M
Bredehorst
Reinhard
R
Voelter
Wolfgang
W
Betzel
Christian
C
D000818:Animals; D001665:Binding Sites; D002645:Chickens; D003300:Copper / Q000378:metabolism*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D008958:Models, Molecular; D046912:Multiprotein Complexes; D010455:Peptides / Q000138:chemical synthesis / Q000235:genetics / Q000378:metabolism; D017096:Prion Diseases / Q000378:metabolism; D011328:Prions / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D011487:Protein Conformation; D013052:Spectrometry, X-Ray Emission
D046912:Multiprotein Complexes; D010455:Peptides; D011328:Prions; D003300:Copper