NR ATHL
AU Lutz,J.; Brabeck,C.; Lingappa,V.R.; Bürkle,A.
TI Membrane topology assessment of mutated prion proteins with micro-deletions in the transmembrane domain 1 (TM-1)
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Cell Biology of PrPc and PrPsc CELL-17
PT Konferenz-Poster
AB
A mutation in the transmembrane domain of PrP (TM-1) is implicated in GSS, resulting in an enhanced frequency of a transmembrane form (CtmPrP). CtmPrP has thus been postulated to be a neurotoxic intermediate in prion diseases besides PrPsc (1, 2). Previously, we have described a mutant of murine PrP, termed PrPDelta 114-121, that lacks 8 amino acids within TM-1 and inhibits the accumulation of PrPsc in Neuro2a cells in a trans-dominantl fashion (3).
We hypothesize that this region is critical for inserting PrP into the membrane, and deletions within this region should lead to the complete loss of transmembrane PrP versions, which has already been shown for mutants lacking the entire TM-1 domain (4).
To verify our hypothesis, we currently established an in vitro assay to assess differences in the membrane topology between different mutants, carrying micro-deletions from two to eight amino acids within the most highly conserved part of TM-1, between codons 114 and 121. This results will be discussed.
1. Hegde, R. S., J. A. Mastrianni, M. R. Scott, K. A. DeFea, P. Tremblay, M. Torchia, S. J. DeArmond, S. B. Prusiner, and V. R. Lingappa. 1998. A transmembrane form of the prion protein in neurodegenerative disease. Science 279:827-34.
2. Hegde, R. S., P. Tremblay, D. Groth, S. J. DeArmond, S. B. Prusiner, and V. R. Lingappa. 1999. Transmissible and genetic prion diseases share a common pathway of neurodegeneration. Nature 402:822-6.
3. Hölscher, C., U. C. Bach, and B. Dobberstein. 2001. Prion protein contains a second endoplasmic reticulum targeting signal sequence located at its C terminus. J Biol Chem 276:13388-94.
4. Hölscher, C., H. Delius, and A. Bürkle. 1998. Overexpression of nonconvertible PrPc delta114-121 in scrapie-infected mouse neuroblastoma cells leads to trans-dominant inhibition of wild-type PrPsc accumulation. J Virol 72:1153-9.
AD J.Lutz, C.Brabeck, A.Bürkle, University of Konstanz, Germany; J.Lutz, V.R.Lingappa, California Pacific Medical Center, CA, USA
SP englisch
PO Deutschland