NR ATQZ
AU Tabrett,C.A.; Sanejouand,Y.H.; Schmidt,B.J.; Hogg,P.J.
TI Autolytic Cleavage of the Prion Disulfide-bond: in Search of a Molecular Mechanism
QU International Conference - Prion 2005: Between fundamentals and society's needs - 19.10.-21.10.2005, Congress Center Düsseldorf - Poster Session: Structure of PrP and molecular determinants of infectivity STRCT-15
PT Konferenz-Poster
AB The presence of disulfide-bonds in proteins has long been understood to provide a structural role, stabilizing the protein tertiary structure. It has recently been shown that some disulfide-bonds have evolved to control how proteins work by breaking or forming in a precise way (Hogg PJ. Trends Biochem. Sci. 28, 210-214, 2003). While some proteins may depend on external oxidants/reductants to drive the disulfide-bond formation/cleavage, these effectors may not always be available or have access to the disulfide-bond. Formation of the prion protein domain swapped-dimer involves the cleavage and reformation of two disulfide-bonds, which occurs in the absence of any reducing agent (Knaus KJ et al. Nature Struct. Biol. 8, 770-774, 2001). This finding implies that cleavage of the prion disulfide occurs via an autolytic process. Data mining of disulfide-containing proteins suggest a YE(D)YK(R) motif that can facilitate disulfide-bond cleavage, directed by small structural changes induced by ligand binding or other environmental factors such as temperature. These changes reorient residues of the YE(D)YK(R) motif near the disulfide-bond and have two effects: polarization of the disulfide-bond by the base residue which makes the bond more susceptible to hydrolytic attack, and creating a hydrogen-bonded chain, through the two tyrosines and the acid, that allows for rapid protonation of the thiols so bond cleavage can occur. There is a Y162D178Y163R164 motif near the prion C179-C214 disulfide-bond. We suggest that this motif may be involved in autolytic cleavage of the prion disulfide-bond during formation of the disulfide-linked domain-swapped dimer and possibly also the scrapie form of the protein.
AD C.A.Tabrett, B.J.Schmidt1, P.J.Hogg, Centre for Vascular Research, University of New South Wales and Department of Haematology, Prince of Wales Hospital, Sydney, Australia; Y.H.Sanejouand, Laboratoire de Physique, Ecole Normale Superieure, Lyon, France; P.J.Hogg, Children's Cancer Institute Australia for Medical Research, Randwick, Australia
SP englisch
PO Deutschland