Prion proteins residues

Monte Carlo/simulated annealing (MC/SA) algorithm for sequential assignment in uniformly 13C, 15N-labeled proteins [137]. The two-dimensional (2D) NCACX and NCOCX spectra measured for the fibril samples of full-length Syrian hamster prion protein (residues 23-231) have been analyzed by the MC/SA protocol, from which it has been concluded that the fibril core is formed primarily in the region of residues 173-224 [54]. 

Chan,J. C., Oyler, N. A., Yau, W. M., and Tycko, R. (2005). Parallel beta-sheets and polar zippers in amyloid fibrils formed by residues 10-39 of the yeast prion protein Ure2p. Biochemistry 44, 10669-10680. 

Physical-chemical characteristics of prion proteins are evident after assigning different parameters, including hydrophobicity, charge, and molecular weight to the amino acid residues (Inouye and Kirschner, 1991, 1998) (Table II, Fig. 5). The sequences among different animals... 

F., and Salmona, M. (1994). Conformational polymorphism of the amyloidogenic and neurotoxic peptide homologous to residues 106-126 of the prion protein. / Biol. Chem. 269, 7859-7862. 

Salmona, M., Malesani, P., De Gioia, L., Gorla, S., Bruschi, M., Molinari, A., Della Vedova, F., Pedrotti, B., Marrari, M. A., Awan, T., Bugiani, O., Forloni, G., et at. (1999). Molecular determinants of the physicochemical properties of a critical prion protein region comprising residues 106-126. Biochem.J. 342, 207-214. 

The prion protein, implicated in diseases such as mad cow and Creutzfeldt-Jakob, is another that has been proposed to undergo extensive refolding to form fibrils. In its native, cellular conformation (PrPc), residues 23-124 are... 

NMR characterization of the recombinant mouse,hamster, bovine and human prion proteins showed that all these molecules share a common architecture, consisting of a flexible unstructured N-terminal tail of about 100 residues from position 23 to position 124 attached to a globular domain within residues 125-228. The globular domain contains a double-stranded anti-parallel /1-sheet and three ot-helices (Fig. 6). 

In inherited forms of prion diseases, a mutation in the gene encoding PrP produces a change in one amino acid residue that is believed to make the conversion of PrPG to PrPSc more likely. A complete understanding of prion diseases awaits new information about how prion protein affects brain function. Structural information about PrP is beginning to provide insights into the molecular process that allows the prion proteins to interact so as to alter their conformation (Fig. 2). 

What are the possible adverse consequences of accumulation of the A(3 protein It may cause inflammation by activation of microglia,1157 which may cause damage by release of NO.1206 A(3 may induce death of neurons by apoptosis.1201 1207-1209 A defect in protesomal degradation may be a factor.1208 Both Ap and the prion protein may promote oxidative damage. The brain derives most of its energy from oxidative metabolism, a major source of damaging radicals. Mitochondria are found in dendrites as well as cell bodies.1210 Methionine residues in glycine-rich parts of the AP and prion proteins are suspected as centers of free radical formation.1202 1211... 

Monoclonal antibodies 3F4 (Senetk, St. Louis, MO) and F89/160.1.5 are used for immunostaining of prion protein. The monoclonal antibody 3F4 was developed by Kascsack et al. (1987) and shows immunoreactivity with the epitope around AA 112 of the human prion protein. The monoclonal antibody F89/160.1.5 was developed at the U.S. Department of Agriculture against a synthetic peptide representing residues 146-159 of... 

The antimalarial drug quinacrine and some phenothiazine derivatives, acepro-mazine, chlorpromazine, and promazine, have been used for the treatment of prion diseases (Doh-ura et al., 2000 Korth et al., 2001 May et al., 2003). The molecular mechanism associated with the inhibition of PrPsc formation by quinacrine remains unknown. However, it is proposed that quinacrine binds with human prion protein at the Tyr-225, Tyr-226, and Gln-227 residues of helix 3 (Vogtherr et al., 2003) and provides neuroprotection. Quinacrine may also act as an antioxidant and reduce the toxicity of prP 6 (Turnbull et al., 2003). 

Other IRRAS applications to peptides and proteins. In addition to the pulmonary surfactant system, a variety of other applications employing IRRAS to study peptide and protein conformation and orientation have appeared. The secondary structure conversion of the amyloid (prion)-protein in the normal form into the abnormal form is the main cause of several human and animal diseases, such as Alzheimer s disease [68]. The secondary structure of the first 40 residues of the amyloid protein was detected by circular dichroism (CD) in aqueous solution and with IRRAS at the interface. A stable /1-sheet-enriched state of the amyloid is formed at the air-water interface, in contrast to the initial bulk solution containing high a-helix/random coil and low /l-sheet parts. The change in the pH going from bulk (alkaline pH) to the interface (neutral or slightly acidic pH) can have effects on the conformation at the interface. Another alternative might be the intrinsic hydrophobicity of the air-water interface, which is a hydrophobic-hydrophilic system with air as the hydrophobic part. 

The cellular form of the prion protein, called PrP, is synthesized as a 253 amino acid precursor protein in humans (Figure 29. IB) (Prusiner, 1991). The N-terminal 22 amino acid residues serve as the signal peptide that allows insertion of the nascent PrP peptide into the secretory pathway during biosynthesis. The C-terminal 22 amino acid residues are involved in the covalent addition of the glycosylphosphatidylino-sitol (GPI) moiety to serine at amino acid 231 (i.e., Ser 9-The GPI anchor tethers PrP to the exhacellular side of the plasma membrane. PrP has two N-hnked glycosylation sites (Asn and Asn ) that are the sites of attachment of complex... 

The pathogenesis of another well-known neurodegenerative disease (Jacob Creutzfeld disease) seems to be strongly linked to the presence of prion proteins in the brain. These macromolecules contain multiple Met residues, some of them in close vicinity. Such structure should favour stabilization of MetS as intramolecular (S.-.S) complexes. Since weak intramolecular non-bonded S O and S N interactions have been recently suggested in proteins [14], stabilization of MetS +through formation of S.-.N- and/or S.-.O-complexes might potentially accelerate oxidation processes in proteins.The first experimental evidence... 

Christen B, Perez DR, Homemann S et al (2008) NMR structure of the bank vole prion protein at 20 degrees C contains a structured loop of residues 165-171. J Mol Biol 383 306-312... 

On the experimental front, the structure of PrPSc derived from brain tissue of scrapie-infected transgenic mice expressing GPI-free prion protein was recently examined by the hydrogen/deuterium exchange method [105], In contrast to the models described above, these data indicate that the PrPc >PrPSc conversion involves major refolding of the entire region C-terminal to residue 80-90, and that this region in PrPSc consists of a network of (3-strands and relatively short turns, with no native a-helices present. 

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