β<sub>2</sub>Microglobulin

and, Thomas R. Jahn; Radford, Sheena E.

doi:10.1002/9783527619344.ch26

Cited by 8 publications

(10 citation statements)

References 124 publications

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“…Deposition of ␤ 2 m amyloid fibrils in vivo, predominantly in osteoarticular sites, is associated with dialysis-related amyloidosis (DRA), a complication of long-term dialysis for end stage renal failure (24). Amyloid-like fibrils generated in vitro from pure recombinant ␤ 2 m in seeded or unseeded reactions, commencing from denatured or natively folded protein, were examined using Fourier transform infrared (FTIR) spectroscopy and compared with spectra of natural ␤ 2 m amyloid fibrils isolated from a patient with DRA.…”

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confidence: 99%

A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

Jahn

Tennent

Radford

2008

Journal of Biological Chemistry

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Misfolding and aggregation of normally soluble proteins into amyloid fibrils and their deposition and accumulation underlies a variety of clinically significant diseases. Fibrillar aggregates with amyloid-like properties can also be generated in vitro from pure proteins and peptides, including those not known to be associated with amyloidosis. Whereas biophysical studies of amyloid-like fibrils formed in vitro have provided important insights into the molecular mechanisms of amyloid generation and the structural properties of the fibrils formed, amyloidogenic proteins are typically exposed to mild or more extreme denaturing conditions to induce rapid fibril formation in vitro. Whether the structure of the resulting assemblies is representative of their natural in vivo counterparts, thus, remains a fundamental unresolved issue. Here we show using Fourier transform infrared spectroscopy that amyloid-like fibrils formed in vitro from natively folded or unfolded ␤ 2 -microglobulin (the protein associated with dialysis-related amyloidosis) adopt an identical ␤-sheet architecture. The same ␤-strand signature is observed whether fibril formation in vitro occurs spontaneously or from seeded reactions. Comparison of these spectra with those of amyloid fibrils extracted from patients with dialysisrelated amyloidosis revealed an identical amide I absorbance maximum, suggestive of a characteristic and conserved amyloid fold. Our results endorse the relevance of biophysical studies for the investigation of the molecular mechanisms of ␤ 2 -microglobulin fibrillogenesis, knowledge about which may inform understanding of the pathobiology of this protein.

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A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

Jahn

Tennent

Radford

2008

Journal of Biological Chemistry

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“…Because of its clinical importance and suitable size for examining the relation between protein folding and amyloid formation, ␤2-m has been a target of extensive study on the relation between protein folding and amyloid fibril formation (14)(15)(16)(17)(18). In previous work, we found that a 22-residue K3 peptide (Ser 20 -Lys 41 ), obtained by digesting ␤2-m, spontaneously forms amyloid protofilament-like fibrils in vitro (19).…”

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“…Because the K3 fibrils in 20% (vol͞vol) TFE do not have a superstructure where several protofilaments associate with one another laterally (3), they are a suitable target for analyzing the whole fibril structure, excluding the contribution of the interfibril interactions. Even with a uniformly 13 C, 15 N-labeled sample, we could propose the 3D structure of the fibrils, leading to an atomic-level understanding the protofibril structure and the types of interactions required to stabilize this structure.…”

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“…␤ 2 -Microglobulin (␤2-m), a component of the type I major histocompatibility antigen, forms amyloid fibrils in patients receiving hemodialysis for long periods (14,15). Because of its clinical importance and suitable size for examining the relation between protein folding and amyloid formation, ␤2-m has been a target of extensive study on the relation between protein folding and amyloid fibril formation (14)(15)(16)(17)(18).…”

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3D structure of amyloid protofilaments of β ₂ -microglobulin fragment probed by solid-state NMR

Iwata

Fujiwara

Matsuki

et al. 2006

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

223

221

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Understanding the structure and formation of amyloid fibrils, the filamentous aggregates of proteins and peptides, is crucial in preventing diseases caused by their deposition and, moreover, for obtaining further insight into the mechanism of protein folding and misfolding. We have combined solid-state NMR, x-ray fiber diffraction, and atomic force microscopy to reveal the 3D structure of amyloid protofilament-like fibrils formed by a 22-residue K3 peptide (Ser 20 -Lys 41 ) of ␤2-microglobulin, a protein responsible for dialysis-related amyloidosis. Although a uniformly 13 C, 15 N-labeled sample was used for the NMR measurements, we could obtain the 3D structure of the fibrils on the basis of a large number of structural constraints. The conformation of K3 fibrils was found to be a ␤-strand-loop-␤-strand with each K3 molecule stacked in a parallel and staggered manner. It is suggested that the fibrillar conformation is stabilized by intermolecular interactions, rather than by intramolecular hydrophobic packing as seen in globular proteins. Together with thermodynamic studies of the full-length protein, formation of the fibrils is likely to require side chains on the intermolecular surface to pack tightly against those of adjacent monomers. By revealing the structure of ␤2-microglobulin protofilament-like fibrils, this work represents technical progress in analyzing amyloid fibrils in general through solid-state NMR.2,2,2-trifluoroethanol ͉ amyloid fibril ͉ dialysis-related amyloidosis ͉ protein misfolding ͉ x-ray fiber diffraction

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“…Dialysis-related amyloidosis is a common and serious complication among patients on long term hemodialysis, in which amyloid fibrils of ␤2-m deposit in the synovia of the carpal tunnel (9,15). A 22-residue K3 peptide, corresponding to Ser 20 -Lys 41 of ␤2-m forms protofilament-like fibrils in various solvents including a low concentration of 2,2,2-trifluoroethanol (16 -19).…”

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Flow-induced Alignment of Amyloid Protofilaments Revealed by Linear Dichroism

Adachi

Yamaguchi

Yagi

et al. 2007

Journal of Biological Chemistry

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Amyloid fibrils underlying various serious amyloidoses including Alzheimer and prion diseases form characteristic deposits in which linear fibrils with an unbranched and rigid morphology associate laterally or radially, e.g. radial senile amyloid plaques of amyloid ␤. To clarify the formation of these high order amyloid deposits, studying the rheology is important. A 22-residue K3 peptide fragment of ␤ 2 -microglobulin, a protein responsible for dialysis-related amyloidosis, forms long and homogeneous protofilament-like fibrils in 20% (v/v) 2,2,2-trifluoroethanol and 10 mM HCl (pH ϳ2). Here, using circular dichroism and linear dichroism, we observed the flow-induced alignment of fibrils. Analysis of far-and near-UV linear dichroism spectra suggested that both the net -* transition moment of the backbone carbonyl group and L b transition moment of the Tyr 26 side chain are oriented in parallel to the fibril axis, revealing the structural details of amyloid protofilaments. Moreover, the intensities of flow-induced circular dichroism or linear dichroism signals depended critically on the length and type of fibrils, suggesting that they are useful for detecting and characterizing amyloid fibrils.Although the structural features of amyloid fibrils are of urgent importance (1-3), the high molecular weight and noncrystalline assembly preclude the use of conventional methods, such as x-ray crystallography or multidimensional NMR, to acquire high resolution structural images. Recently, it has been found that amyloid fibrils are, in general, amenable to the magic angle-spinning solid-state nuclear magnetic resonance methods, providing a general view of the atomic level structure in which ␤-strands are stacked in a parallel and registered manner (4 -6). A structure revealed by x-ray diffraction of a crystalline short amyloidogenic peptide was consistent with this view (7).More recently, the mechanical characterization of individual fibrils by atomic force microscopy revealed that the insulin fibrils have a strength and stiffness comparable with that of steel and silk, respectively (8). Among various structural features, although the long and rigid morphology of amyloid fibrils might be responsible for their biological consequences, rheological details remain unknown.␤ 2 -Microglobulin (␤2-m), 4 a typical immunoglobulin domain made of 99 residues, is a target of extensive study because of its clinical importance and suitable size for examining the relationship between protein folding and amyloid formation (9 -14). Dialysis-related amyloidosis is a common and serious complication among patients on long term hemodialysis, in which amyloid fibrils of ␤2-m deposit in the synovia of the carpal tunnel (9, 15). A 22-residue K3 peptide, corresponding to Ser 20 -Lys 41 of ␤2-m forms protofilament-like fibrils in various solvents including a low concentration of 2,2,2-trifluoroethanol (16 -19). Although the efficient fibrillation of intact ␤2-m requires seeding, K3 forms fibrils spontaneously. Furthermore, K3 formed two types of fibr...

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β₂Microglobulin

Cited by 8 publications

References 124 publications

A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

3D structure of amyloid protofilaments of β ₂ -microglobulin fragment probed by solid-state NMR

Flow-induced Alignment of Amyloid Protofilaments Revealed by Linear Dichroism

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β2Microglobulin

Cited by 8 publications

References 124 publications

A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

A Common β-Sheet Architecture Underlies in Vitro and in Vivo β2-Microglobulin Amyloid Fibrils

3D structure of amyloid protofilaments of β 2 -microglobulin fragment probed by solid-state NMR

Flow-induced Alignment of Amyloid Protofilaments Revealed by Linear Dichroism

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β₂Microglobulin

3D structure of amyloid protofilaments of β ₂ -microglobulin fragment probed by solid-state NMR