Conformational Stability of PrP Amyloid Fibrils Controls Their Smallest Possible Fragment Size

Sun, Ying; Makarava, Natallia; Lee, Cheng-I; Laksanalamai, Pongpan; Robb, Frank T.; Baskakov, Ilia V.

doi:10.1016/j.jmb.2007.12.053

Cited by 62 publications

(69 citation statements)

References 46 publications

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“…However, its strong effect of agitation has recently been found to accelerate the fibril nucleation of several proteins and peptides (14)(15)(16)(17)(18). Interestingly, amyloid fibrils produced by ultrasonicationinduced fibrillation were very short with apparently similar lengths as determined by AFM (15,19), suggesting that short fibrils of homogeneous molecular size are formed efficiently under ultrasonication in combination with the opposing effects of fragmentation and of nucleation (Fig. 1).…”

mentioning

confidence: 93%

Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils

Chatani

Lee

Yagi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

144

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Because of the insolubility and polymeric properties of amyloid fibrils, techniques used conventionally to analyze protein structure and dynamics have often been hampered. Ultrasonication can induce the monomeric solution of amyloidogenic proteins to form amyloid fibrils. However, ultrasonication can break down preformed fibrils into shorter fibrils. Here, combining these 2 opposing effects on ␤2-microglobulin (␤2-m), a protein responsible for dialysisrelated amyloidosis, we present that ultrasonication pulses are useful for preparing monodispersed amyloid fibrils of minimal size with an average molecular weight of Ϸ1,660,000 (140-mer). The production of minimal and monodispersed fibrils is achieved by the free energy minimum under competition between fibril production and breakdown. The small homogeneous fibrils will be of use for characterizing the structure and dynamics of amyloid fibrils, advancing molecular understanding of amyloidosis.␤2-microglobulin ͉ dialysis-related amyloidosis ͉ protein misfolding ͉ analytical ultracentrifugation A myloid fibrils are supramolecular assemblies exhibiting a long unbranched fibrillar morphology Ϸ10 nanometers in diameter, the deposition of which is associated with Ͼ30 degenerative diseases including Alzheimer's disease, prion disease, and dialysis-related amyloidosis (1-3). The past decade has seen progress in our biophysical understanding of amyloid fibrils using various approaches including solution and solid state NMR (4-6) and X-ray crystallography (7,8). However, the polymeric properties of amyloid fibrils, where huge size and heterogeneous nature result in insoluble and noncrystalline assemblies, are an obstacle to techniques such as X-ray crystallography, solution NMR spectroscopy and other conventional spectroscopic measurements. To overcome the analytical problems confronting studies of amyloid fibrils, it is worth establishing a strategy for producing monodispersed samples of amyloid fibrils. If amyloid fibrils of a well-defined molecular weight and improved solubility are formed reproducibly, a more general application of various types of fibril samples to a series of preexisting spectroscopic measurements will be accomplished.As a strategy to produce amyloid fibrils of uniform and minimal size, ultrasonication has several potential applications. Although ultrasonication was originally used to prepare seeds from preformed fibrils (9), which were further applied to the amplification of infectious prion proteins (10, 11), ultrasonication-dependent fragmentation is becoming an important approach to analyzing the properties of fibrils (12, 13). However, its strong effect of agitation has recently been found to accelerate the fibril nucleation of several proteins and peptides (14-18). Interestingly, amyloid fibrils produced by ultrasonicationinduced fibrillation were very short with apparently similar lengths as determined by AFM (15,19), suggesting that short fibrils of homogeneous molecular size are formed efficiently under ultrasonication in combination with the...

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mentioning

confidence: 93%

Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils

Chatani

Lee

Yagi

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

130

144

View full text Add to dashboard Cite

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“…UP in: neurons (in MNDs, NPD, AD, PD, CJD) [27][28][29][30][31][32] UP in: reactive glial cells, microglia, oligodendrocytes [11,13,16,17,33,34] þ þ [1] no [1] no [21] PD: þ þ [35] ALD: þ þ [36] cytoskeleton stabilization; maintaining the proper refractive index in the lens [37,38] (Continued. )…”

Section: Introductionmentioning

confidence: 99%

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Carra

Rusmini

Crippa

et al. 2013

Phil. Trans. R. Soc. B

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The family of the mammalian small heat-shock proteins consists of 10 members (sHSPs/HSPBs: HSPB1–HSPB10) that all share a highly conserved C-terminal alpha-crystallin domain, important for the modulation of both their structural and functional properties. HSPB proteins are biochemically classified as molecular chaperones and participate in protein quality control, preventing the aggregation of unfolded or misfolded proteins and/or assisting in their degradation. Thus, several members of the HSPB family have been suggested to be protective in a number of neurodegenerative and neuromuscular diseases that are characterized by protein misfolding. However, the pro-refolding, anti-aggregation or pro-degradative properties of the various members of the HSPB family differ largely, thereby influencing their efficacy and protective functions. Such diversity depends on several factors, including biochemical and physical properties of the unfolded/misfolded client, the expression levels and the subcellular localization of both the chaperone and the client proteins. Furthermore, although some HSPB members are inefficient at inhibiting protein aggregation, they can still exert neuroprotective effects by other, as yet unidentified, manners; e.g. by maintaining the proper cellular redox state or/and by preventing the activation of the apoptotic cascade. Here, we will focus our attention on how the differences in the activities of the HSPB proteins can influence neurodegenerative and neuromuscular disorders characterized by accumulation of aggregate-prone proteins. Understanding their mechanism of action may allow us to target a specific member in a specific cell type/disease for therapeutic purposes.

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“…The use of a low chaotropic concentration (∼2 M urea or guanidium chloride) is one of the strategies which can lead to the formation of amyloid fibrils [4,76,122]. Recently the Baskakov's group showed that fragmentation of amyloid fibrils under different physicochemical constraints such as temperature or shaking rate leads to the formation of fibrillar fragments whose size is correlated to the conformationional stability of prion fibrils [68,120].…”

Section: Linkage Between Prp Conformational Dynamics and Prion Pathologymentioning

confidence: 99%

Misfolding of the prion protein: linking biophysical and biological approaches

2008

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-Prion diseases are a group of neurodegenerative diseases that can arise spontaneously, be inherited, or acquired by infection in mammals. The propensity of the prion protein to adopt different structures is a clue to its pathological and perhaps biological role too. While the normal monomeric PrP is well characterized, the misfolded conformations responsible for neurodegeneration remain elusive despite progress in this field. Both structural dynamics and physico-chemical approaches are thus fundamental for a better knowledge of the molecular basis of this pathology. Indeed, multiple misfolding pathways combined with extensive posttranslational modifications of PrP and probable interaction(s) with cofactors call for a combination of approaches. In this review, we outline the current physico-chemical knowledge explaining the conformational diversities of PrP in relation with postulated or putative cellular partners such as proteic or non-proteic ligands.

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Conformational Stability of PrP Amyloid Fibrils Controls Their Smallest Possible Fragment Size

Cited by 62 publications

References 46 publications

Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils

Ultrasonication-dependent production and breakdown lead to minimum-sized amyloid fibrils

Different anti-aggregation and pro-degradative functions of the members of the mammalian sHSP family in neurological disorders

Misfolding of the prion protein: linking biophysical and biological approaches

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