Down the Cause of Mad Cow Disease
Source of Article: http://www.physorg.com/news142595542.html
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.
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.
Citation: Christian F. W. Becker, Semisynthesis of
a Glycosylphosphatidylinositol-Anchored Prion Protein, Angewandte
Chemie International Edition 2008, 47, No. 43,
8215–8219, doi: 10.1002/anie.200802161