Structural Properties of Gerstmann-Sträussler-Scheinker Disease Amyloid Protein

Salmona, Mario; Morbin, Michela; Massignan, Tania; Colombo, Laura; Mazzoleni, Giulia; Capobianco, Raffaella; Diomede, Luisa; Thaler, Florian; Mollica, Luca; Musco, Giovanna; Kourie, Joseph J.; Bugiani, Orso; Sharma, Deepak; Inouye, Hideyo; Kirschner, Daniel A.; Forloni, Gianluigi; Tagliavini, Fabrizio

doi:10.1074/jbc.m307295200

Cited by 80 publications

(58 citation statements)

References 44 publications

(62 reference statements)

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“…Distance restraints (Table II) enforced interstrand distances between different layers orthogonal to the fibril axis to 4.8 Å , in agreement with X-ray diffraction patterns of mammalian prions 37 and amyloid fibrils of PrP(82-146). 38 Hydrogen-bond distance restraints for parallel, in-register alignment-as shown by solid-state NMR spectroscopy of humPrP(23-144) 31 -were used. In addition, the location of b-strands as identified by solid-state NMR chemical shifts (Supporting Information Fig.…”

Section: Resultsmentioning

confidence: 99%

Determination of amyloid core structure using chemical shifts

Skora

Zweckstetter

2012

Protein Science

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Amyloid fibrils are the pathological hallmark of a large variety of neurodegenerative disorders. The structural characterization of amyloid fibrils, however, is challenging due to their non-crystalline, heterogeneous, and often dynamic nature. Thus, the structure of amyloid fibrils of many proteins is still unknown. We here show that the structure calculation program CS-Rosetta can be used to obtain insight into the core structure of amyloid fibrils. Driven by experimental solid-state NMR chemical shifts and taking into account the polymeric nature of fibrils CS-Rosetta allows modeling of the core of amyloid fibrils. Application to the Y145X stop mutant of the human prion protein reveals a left-handed b-helix.

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Section: Resultsmentioning

confidence: 99%

Determination of amyloid core structure using chemical shifts

Skora

Zweckstetter

2012

Protein Science

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“…The deposition of aggregated PrP species in rod-like amyloidogenic structures is a common feature of CJD (Prusiner 1998) and other prion disorders (Salmona et al 2003). Similarly to Ab, small PrP oligomeric structures are the most infectious prion species (Silveira et al 2005).…”

Section: The Deposition Of Aggregates Is a Hallmark Of Neurodegeneratmentioning

confidence: 99%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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“…Electron microscopy, on the other hand, estimated the diameter of amyloid fibrils of the Y145X and Q160X stop mutants and of the peptide encompassing residues 108-143 [humPrP(108-143)] as 7-9 nm. 6,7,16 A diameter of 7-9 nm could only be reached for a single filament of humPrP(108-143) when the peptide would be fully extended, in disagreement to the identified β-helix structure. Thus, it is likely that multiple filaments come together in amyloid fibrils of prion stop mutants as suggested for N-terminally truncated PrP Sc .…”

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confidence: 99%