cDNA sequence and tissue expression of Fugu rubripes prion protein-like: a candidate for the teleost orthologue of tetrapod PrPs

Suzuki, Tohru; Kurokawa, Tadahide; Hashimoto, Hisashi; Sugiyama, Munehiro

doi:10.1016/s0006-291x(02)00546-6

Cited by 66 publications

(60 citation statements)

References 11 publications

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“…It is also interesting to observe that the residues immediately preceding helix I show similar upfield CЈ chemical shifts. Peptides that contain residues 138 -141 but not helix I, form fibrils more readily than peptides that are devoid of this region (70), and it has been suggested that this region of the protein may provide a nucleus for the oligomerization (67).…”

Section: Resultsmentioning

confidence: 99%

Conformational Properties of β-PrP

Hosszu

Trevitt

Jones

et al. 2009

Journal of Biological Chemistry

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Prion propagation involves a conformational transition of the cellular form of prion protein (PrP C ) to a disease-specific isomer (PrP Sc ), shifting from a predominantly ␣-helical conformation to one dominated by ␤-sheet structure. This conformational transition is of critical importance in understanding the molecular basis for prion disease. Here, we elucidate the conformational properties of a disulfide-reduced fragment of human PrP spanning residues 91-231 under acidic conditions, using a combination of heteronuclear NMR, analytical ultracentrifugation, and circular dichroism. We find that this form of the protein, which similarly to PrP Sc , is a potent inhibitor of the 26 S proteasome, assembles into soluble oligomers that have significant ␤-sheet content. The monomeric precursor to these oligomers exhibits many of the characteristics of a molten globule intermediate with some helical character in regions that form helices I and III in the PrP C conformation, whereas helix II exhibits little evidence for adopting a helical conformation, suggesting that this region is a likely source of interaction within the initial phases of the transformation to a ␤-rich conformation. This precursor state is almost as compact as the folded PrP C structure and, as it assembles, only residues 126 -227 are immobilized within the oligomeric structure, leaving the remainder in a mobile, random-coil state.

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Section: Resultsmentioning

confidence: 99%

Conformational Properties of β-PrP

Hosszu

Trevitt

Jones

et al. 2009

Journal of Biological Chemistry

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“…In fact, peptides that contain the bulky residues IIHF immediately preceding Gly-142, but do not include helix 1, form fibrils more readily than for example peptides containing only the alanine-rich part preceding the COOH-terminal domain of PrP. 3 This raises the possibility for a mechanism of PrP Sc formation in which a nucleus for oligomerization is formed by hydrophobic contacts at solventexposed parts of the protein, such as I138-IHF or ␤-strand 1 (Tyr-128-ML). Contact formation and subsequent extension of the ␤-sheet nucleus lead to a change in the chemical environment of helix 1 causing it to unfold at least partially and change into a conformation presumably consisting of sheet-and turnelements.…”

Section: The Interactions Rendering Prp Helix 1 Stable Are Responsiblmentioning

confidence: 99%

“…Its cellular form, PrP C , is a highly conserved cell surface glycoprotein of 230 amino acids expressed in all of the mammals studied so far as well as in several species of fish and birds (2,3). The physiological function of PrP C is not yet fully understood.…”

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confidence: 99%

CD and NMR Studies of Prion Protein (PrP) Helix 1

Ziegler

Sticht

Marx

et al. 2003

Journal of Biological Chemistry

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The conversion of prion helix 1 from an ␣-helical into an extended conformation is generally assumed to be an essential step in the conversion of the cellular isoform PrP C of the prion protein to the pathogenic isoform PrP Sc . Peptides encompassing helix 1 and flanking sequences were analyzed by nuclear magnetic resonance and circular dichroism. Our results indicate a remarkably high instrinsic helix propensity of the helix 1 region. In particular, these peptides retain significant helicity under a wide range of conditions, such as high salt, pH variation, and presence of organic co-solvents. As evidenced by a data base search, the pattern of charged residues present in helix 1 generally favors helical structures over alternative conformations. Because of its high stability against environmental changes, helix 1 is unlikely to be involved in the initial steps of the pathogenic conformational change. Our results implicate that interconversion of helix 1 is rather representing a barrier than a nucleus for the PrP C 3 PrP Sc conversion.Prion protein, PrP, 1 is probably the disease-causing agent of transmissible spongiform encephalopathies such as bovine spongiform encephalopathy in cattle or Creutzfeldt-Jakob disease in man (1). Its cellular form, PrP C , is a highly conserved cell surface glycoprotein of 230 amino acids expressed in all of the mammals studied so far as well as in several species of fish and birds (2, 3). The physiological function of PrP C is not yet fully understood. PrP C seems to be involved in the maintenance of proper presynaptic copper levels as well as in protecting neurons from oxidative stress (4, 5). In addition, the physiological function of PrP C could be associated with higher neurological functions such as learning and memory (5). According to the protein-only hypothesis, disease is caused by accumulation of a misfolded pathogenic isoform, PrP Sc , which is the result of an irreversible large scale conformational change of PrP C . Although PrP C is largely ␣-helical and soluble in polar solvents and sensitive to protease K digestion, PrP Sc consists mostly of ␤-sheets, is soluble only in nonpolar, denaturing solvents, and is resistant to digestion with protease K (6). PrP Sc forms fibrillar aggregates similar to other amyloid fibrils (7). Accumulation of PrP Sc aggregates is accompanied by astrocytosis and gliosis in central nervous tissue, which in turn result in vacuoles in the brains of patients.The solution structures of human PrP-(23-230), huPrP (8), mouse PrP-(121-231) (9), bovine PrP-(23-230) (10), and Syrian hamster PrP-(29 -231) (11) have been determined by NMR spectroscopy. They possess a high degree of structural conservation consistent with the high sequence identity of these proteins. Prion proteins consist of a flexible NH 2 -terminal domain spanning residues 23-124 (huPrP C -numbering scheme), which is largely disordered. This region includes an octapeptide sequence that is repeated four times from residues 60 to 92 and that is likely to bind copper (4). This part al...

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“…However, alignments of human and mammalian PRNP sequences indicate that codons located between residues 90 and 130 influence the transmissibility of prions in mammals, including humans (Schatzl et al, 1995). In addition, some paralogue genes have been described in chicken, amphibians, reptiles and fish (Gabriel et al, 1992;Simonic et al, 2000;Strumbo et al, 2001;Suzuki et al, 2002) 2. Tissue and cellular expression of PrP c : from the whole organism to the neuronal synapse.…”

Section: Introductionmentioning

confidence: 99%