W0249
Crystallographic Studies of the Human Prion Protein.
Karen J. Knaus1,2, Rune Hartmann1, Lizamma
Antony1, David Vanik3, Manuel Morillas3,
Wieslaw Swietnicki3, Witold K. Surewicz3,5,6 and Vivien C.
Yee1,2,4, 1Dept. of Molecular Cardiology and Center for
Structural Biology, Lerner Research Institute, Cleveland Clinic Foundation,
2Dept. of Chemistry, Cleveland State Univ., Depts. of
3Pathology, 4Pharmacology, 5Chemistry and
6Physiology and Biophysics, Case Western Reserve Univ.
Prions are novel infectious particles that are believed to be
composed entirely of proteins. They have been found to play an important role in
the pathogenesis of neurodegenerative diseases that can be infectious,
inherited, and sporadic. The key event in disease transmission is believed to be
the structural conversion of PrPC (predominantly α-helical,
monomeric form) to PrPSc (predominantly β-sheet enriched,
oligomeric form of the protein). During the conversion of PrPC to
PrPSc, it is believed that the protein obtains a marked increase in
β-sheet secondary structure. The predominantly β-sheet
PrPSc isoform can then further oligomerize and eventually deposit
itself as fibrils, β-amyloid plaques, or other insoluble aggregates in the
brains of diseased patients. Many recent investigations of PrP have been
targeted at studying the differences between the two isoforms and their
respective roles in the PrPC to PrPSc conversion. Thus
structural studies of the prion protein (PrP) seem to be a logical starting
point for understanding prion disease mechanism. Previously determined high
resolution NMR structures of bacterially expressed PrP from mouse, hamster, cow
and human have been useful in determining a monomeric predominantly
α-helical state of the protein. Our crystallographic studies of recombinant
human prion proteins, focusing on wild-type and pathogenic mutants, reveals
additional structural features which may be important in understanding the
PrPC to PrPSc conversion and/or aggregation properties of
the protein.