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Synthetic human prion protein octapeptide repeat binds to the proteinase K active site
Authors:Georgieva Dessislava  Rypniewski Wojciech  Echner Hartmut  Perbandt Markus  Koker Mirjam  Clos Joachim  Redecke Lars  Bredehorst Reinhard  Voelter Wolfgang  Genov Nicolay  Betzel Christian
Institution:Zentrum für Experimentelle Medizin, Institut für Biochemie und Molekularbiologie I, Universit?tsklinikum Hamburg-Eppendorf, c/o DESY, Notkestrasse 85, Geb. 22a, 22603 Hamburg, Germany.
Abstract:Proteinase K is widely used in tests for the presence of infectious prion protein causing fatal spongiform encephalopathies. To investigate possible interactions between the enzyme and the functionally important N-terminal prion domain, we crystallized mercury-inhibited proteinase K in the presence of the synthetic peptides GGGWGQPH and HGGGW. The octapeptide sequence is identical to that of a single octapeptide repeat (OPR) from the physiologically important OPR region. Here, we present the first direct evidence for the complex formation between a proteolytic enzyme and a segment of human prion molecule. The X-ray structures of the complexes at 1.4 and 1.8A resolution, respectively, revealed that in both cases the segment GGG is strongly bound as a real substrate at the substrate recognition site of the proteinase forming an antiparallel beta-strand between the two parallel strands of Asn99-Tyr104 and Ser132-Gly136. The complex is stabilized through an extended H-bonding network.
Keywords:Prion protein  Scrapie isoform  Proteinase K  Octapeptide repeats  X-ray  Substrate recognition
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