A new form of amyloid protein associated with chronic hemodialysis was identified as β2-microglobulin

Gejyo, F; Yamada, Takao; Odani, Sumiko; Nakagawa, Yoichi; Arakawa, Masaaki; Kunitomo, Tadayoshi; Kataoka, Hiroaki; Suzuki, Makiko; Hirasawa, Yoshihei; Shirahama, Tsuranobu; Cohen, Alan S.; Schmid, Kurt Werner

doi:10.1016/0006-291x(85)91948-5

Cited by 973 publications

(520 citation statements)

References 16 publications

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“…5 Amyloid formation of b2m is strongly enhanced in conditions that destabilize its globular structure. 6 This can be achieved in Vitro by acid denaturation, with two distinct intermediate states being formed under acidic conditions.…”

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confidence: 99%

Molten Globule Precursor States Are Conformationally Correlated to Amyloid Fibrils of Human β-2-Microglobulin

2010

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Misfolding intermediates play a key role in defining aberrant protein aggregation and amyloid formation in more than 15 different human diseases. However, their experimental characterization is challenging due to the transient nature and conformational heterogeneity of the involved states. Here, we demonstrate that direct carbon-detected NMR experiments allow observation, assignment, and structural analysis of molten globule amyloid intermediates that are severely broadened by conformational exchange. The method is used to characterize the structure and dynamics of partially unfolded intermediates of the 99-residue protein -2-microglobulin, which is the major component of insoluble aggregates occurring in dialysis-related amyloidosis. Comparison of the conformational properties of the molten globule-like intermediates with levels of deuterium incorporation into amyloid fibrils of -2-microglobulin revealed a close relationship between the conformational properties of the metastable intermediates and the -sheet-rich insoluble aggregates of -2-microglobulin.Misfolding intermediates play a key role in defining aberrant protein aggregation and amyloid formation in more than 15 different human diseases. 1,2 However, the experimental characterization of the conformation of amyloid intermediates is challenging due to their transient nature and conformational heterogeneity. 3,4 This severely limits our knowledge about the relation of the conformation of the precursor states to the structure of amyloid fibrils.Dialysis-related amyloidosis is a protein misfolding disease resulting from deposition of amyloid aggregates in skeletal tissue that contain fibrils of the 99-residue-long protein -2-microglobulin (b2m). 5 Amyloid formation of b2m is strongly enhanced in conditions that destabilize its globular structure. 6 This can be achieved in Vitro by acid denaturation, with two distinct intermediate states being formed under acidic conditions. The highest population of the partially unfolded intermediate occurs at pH 3.6, where also the rate of fibril formation reaches a maximum. 7 However, long and straight amyloid fibrils resembling those extracted from patients are formed from a precursor state formed at pH 2.5. 8,9 Here, we compare the conformational properties of these two partially unfolded intermediates with single-residue resolution and demonstrate that a close relationship exists between the structure and dynamics of the amyloid precursor species and the morphology of mature fibrils of b2m.At pH 2.5 b2m is highly unfolded, the majority of resonances are observed in 1 H-15 N HSQC spectra (Supporting Information, Figure 1) and can be assigned to individual residues. 10 In contrast, only about 40-60 resolved peaks on top of a broad hump of unresolved signal intensity (visible at lower contour levels) could be observed at pH 3.6 ( Figure 1a). 11 To obtain sequence-specific information about the pH 3.6 intermediate, we tested direct 13 C detection. 12-14 Direct carbon detection was previously successfully used fo...

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Molten Globule Precursor States Are Conformationally Correlated to Amyloid Fibrils of Human β-2-Microglobulin

2010

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“…Since the original identification of &-microglobulin (P2m) in the carpal tunnel tissues of hemodialysis patients (2), researchers have found this unique type of amyloid in synovium, cystic bone lesions, and multiple visceral organs in these patients (3,4). The inability of conventional dialysis membranes to remove P2m, lack of normal renal catabolism, and perhaps even stimulated production in certain hemodialysis patients results in serum levels of P2m that are 20-30 times higher than normal (2,4,5).…”

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confidence: 99%

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1991

Arthritis & Rheumatism

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The patient is a 68-year-old man with end-stage renal disease, in whom kidney transplantation had been unsuccessful. He had been receiving hemodialysis for 20 years. He had had a carpal tunnel release and now presents with increasing pain and swelling in the shoulders, wrists, knees, and hips.Well-defined erosion of the femoral neck with preservation of the femoral head suggests the presence Radiologic findingsAn anteroposterior view of the pelvis (Figure 1) shows multiple surgical clips, generalized osteopenia, and vascular calcifications. These findings are consistent with the patient's history of chronic renal failure and transplantation. In addition, there are prominent erosions of the femoral necks bilaterally, with good preservation of the hip cartilage. A well-defined left acetabular lucent lesion is present (Figure 2).

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“…In one group of precursors, overproduction or failure to excrete an intact molecule that has a concentration dependent tendency to misfold, for example, ANF, b 2 microglobulin and IAPP, is sufficient. [20][21][22] These molecules require no other processing to form fibrils, although partial proteolysis might enhance their fibril forming capacity. In a second class, the intact molecule is not amyloidogenic but abnormal site specific proteolysis generates an amyloidogenic fragment, e.g Alzheimers Disease (Ab).…”

Section: Mechanisms Of Amyloidogenesis In Humansmentioning

confidence: 99%

The genetics of the amyloidoses: interactions with immunity and inflammation

Buxbaum

2006

Genes Immun

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Historically, the amyloidoses have been associated with inflammation and the immune response. From Virchow's original description in human pathologic inflammatory states through their identification in horses used to produce antitoxin to their frequent occurrence in the course of multiple myeloma and a somewhat abortive designation as 'gammaloid', the disorders were felt to have an inflammatory origin. These presumptive associations antedated the availability of a reliable method for tissue extraction that would allow chemical analysis of the major deposited molecules. With the identification of the multiple precursors and the realization that most were not intrinsic elements of immune/inflammatory pathways, the investigative emphasis shifted to the analysis of the biophysical events involved in aggregation and fibril formation. As more in vivo models and better tools for examination of tissues have become available, it appears as if inflammation may participate as both a response to, and an amplifier of, the effects of the fibrillar aggregates. Hence, while only a limited number of amyloid protein precursors are involved in immunity and inflammation per se, host defense, in its broadest sense, is likely to be involved in the clinically relevant amyloidoses. Further it now appears that harnessing the immune respone in an appropriate fashion may be able to play a role in treatment.

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A new form of amyloid protein associated with chronic hemodialysis was identified as β2-microglobulin

Cited by 973 publications

References 16 publications

Molten Globule Precursor States Are Conformationally Correlated to Amyloid Fibrils of Human β-2-Microglobulin

Molten Globule Precursor States Are Conformationally Correlated to Amyloid Fibrils of Human β-2-Microglobulin

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The genetics of the amyloidoses: interactions with immunity and inflammation

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