Understanding the complex mechanisms of β₂‐microglobulin amyloid assembly

Abstract

Several protein misfolding diseases are associated with the conversion of native proteins into ordered protein aggregates known as amyloid. Studies of amyloid assemblies have indicated that non-native proteins are responsible for initiating aggregation in vitro and in vivo. Despite the importance of these species for understanding amyloid disease, the structural and dynamic features of amyloidogenic intermediates and the molecular details of how they aggregate remain elusive. This review focuses on recent advances in developing a molecular description of the folding and aggregation mechanisms of the human amyloidogenic protein β2-microglobulin under physiologically relevant conditions. In particular, the structural and dynamic properties of the non-native folding intermediate IT and its role in the initiation of fibrillation and the development of dialysis-related amyloidosis are discussed.

Application and use of differential scanning calorimetry in studies of thermal fluctuation associated with amyloid fibril formation

“…Recently, Goto and colleagues closely studied the thermal behaviors of amyloid fibrils formed from β 2 -m using DSC (Sasahara et al 2005(Sasahara et al , 2006(Sasahara et al , 2007a(Sasahara et al , b, 2009. Amyloid fibril formation of β 2 -m, which is the light chain of the major histocompatibility complex class I molecules (Bjorkman et al 1987), has been studied extensively because of its clinical importance associated with dialysis-related amyloidosis Radford et al 2005;Stoppini et al 2005;Yamamoto and Gejyo 2005;Eichner and Radford 2011b). It is now known that at pH 2.5, β 2 -m is acidunfolded, and two types of fibrils are formed through a lag phase-and a non-lag phase-dependent kinetics, based on a careful choice of salt concentrations (Hong et al 2002;Gosal et al 2005;Raman et al 2005).…”

Ultrasonication: An Efficient Agitation for Accelerating the Supersaturation-Limited Amyloid Fibrillation of Proteins

“…[11][12][13][14][15][16][17][18][19] Studies on 2-m illustrate a basic mechanism of amyloid fibrillation. Dialysis-related amyloidosis is a common and serious complication in patients receiving hemodialysis for more than 10 years.…”

“…Recently, the mechanism of amyloid fibrillation under physiological pH conditions has been focused on. 18,[25][26][27][28] Amyloid fibrillation consists of nucleation and growth. 16,24,29,30) The nucleation process, in which a number of monomers associate to form a minimal fibril unit, does not readily occur.…”

Camelid single-domain antibody fragments: Uses and prospects to investigate protein misfolding and aggregation, and to treat diseases associated with these phenomena

“…The dialysis-related amyloidosis (DRA) is associated, at least in part, with the increase in b2-microglobulin (b2m) concentration (up to 60-fold) during long-term haemodialysis, which leads to the aggregation of b2m into insoluble amyloid fibrils that accumulate extracellularly in bones and joints [84,90,91]. This deposition causes painful arthropathy, cysts and pathologic fracture.…”

“…They include the age of the patient, duration of renal dysfunction, interactions with a range of molecules (e.g. copper ions, glycosaminoglycans and collagen), and the formation of one or more amyloidogenic intermediates [90,91]. A b2m conformer with a nonnative peptidyl-Pro32 trans peptide bond is, in particular, thought to serve as a direct precursor of dimeric species and oligomers that accumulate in the early phase of fibril formation [92].…”