Angewandte Chemie International Edition 2008, 47, 8215–8219
Tracking Down the Cause of Mad Cow Disease
First synthetic prion protein with an anchor
Contact: Christian F. W. Becker, Max-Planck-Institut für molekulare Physiologie, Dortmund (Germany)
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Semisynthesis of a Glycosylphosphatidylinositol-Anchored Prion Protein
The cause of diseases such as BSE in cattle and Creutzfeld–Jakob disease in
humans is a prion protein. This protein attaches to cell membranes by
way of an anchor made of sugar and lipid components (a
glycosylphosphatidylinositol, GPI) anchor. The anchoring of the prions
seems to have a strong influence on the transformation of the normal
form of the protein into its pathogenic form, which causes scrapie and
mad cow disease. A team headed by Christian F. W. Becker at the TU
Munich and Peter H. Seeberger at the ETH Zurich has now “recreated” the
first GPI-anchored prion in the laboratory. As they report in the
journal Angewandte Chemie, they have been able to develop a new
general method for the synthesis of anchored proteins.
The isolation of a complete prion protein that includes the anchor has not yet
been achieved, nor has it been possible to produce a synthetic
GPI-anchored protein. The function of the GPI anchor has thus remained
in the dark. A new synthetic technique has now provided an important
breakthrough for the German and Swiss team of researchers.
The sugar component of natural prion GPI anchors consists of five sugar
building blocks, to which further sugars are attached through branches.
Details of the lipid component have not been determined before. As a
synthetic target, the researchers thus chose a construct made of the
five sugars and one C18-lipid chain and worked out the
corresponding synthetic route. First, the anchor was furnished with the
sulfur-containing amino acid cysteine. The prion protein was produced
with the use of bacteria and was given an additional thioester (a
sulfur-containing group). The centerpiece of the new concept is the
linkage of the protein and anchor by means of a native chemical
ligation, in which the cysteine group reacts with the thioester. This
allowed the prion protein to firmly attach to the vesicle membranes by
way of the artificial anchor.
This new concept will allow production of sufficient quantities of proteins
modified with GPI anchors for in-depth studies. Experiments with the
artificial GPI prion protein should help to clarify the influence of
membrane association on conversion of the protein into the pathogenic
scrapie form. This should finally make it possible to track down the
infectious form of the prion.