NR AOVS
AU Leliveld,S.R.; Klingenstein,R.; Lingappa,V.; Korth,C.
TI Copper-dependent molecular interactions of the prion protein
QU International Conference - Prion diseases: from basic research to intervention concepts - TSE-Forum, 08.10.-10.10.2003, Gasteig, München - Poster session - BR-32
PT Konferenz-Poster
AB
Prions cause a range of transmissible neurodegenerative diseases in humans and animals. A pivotal step in the disease process is the conversion of the normal membrane-anchored prion protein (PrPc) to the conformational isoform PrPsc. The subsequent accumulation of PrPsc aggregates in the brain is associated with neuronal cell death. The physiological role of PrPc and that of its topological isoforms CtmPrP, SecPrP, and NtmPrP is currently unknown. However, as the N-terminal domain of PrP was shown to bind copper, the biological function of PrP isoforms may be modulated by copper binding. The metal-binding motif of PrP consists of five repeats of the sequence PHGGGWGQ, that cooperatively bind copper ions.
Here, we report on the production and characterization of the monoclonal antibody 7VC that recognizes the PrP octarepeat region in a copper concentration-dependent manner. We found that 7VC displays a markedly higher affinity for copper-depleted PrP than for copper-bound PrP. Using surface plasmon resonance and immunoprecipitation of PrP from brain homogenates, we determined that the affinity of mAB 7VC for the PrP N-terminus decreased with increasing length of octarepeats. These findings lead us to conclude that 7VC detects copper-associated conformational changes of PrP. Moreover, these results indicate that such changes also occur in vivo and suggest that copper-associated conformational changes in PrP isoforms regulate their biological function through interactions with other cellular proteins.
Supported by the BMBF, Germany, and a grant from the NINDS of the NIH, USA
AD Rutger Leliveld, Ralf Klingenstein, Carsten Korth, Heinrich Heine University Düsseldorf, Institute for Neuropathology, Germany; Vishwanath Lingappa, University of California San Francisco, Department of Physiology and Medicine
SP englisch
PO Deutschland