Systemic amyloidosis: lessons from β2-microglobulin.
Bottom Line: Its genetic variant D76N causes a very rare form of familial systemic amyloidosis.These two types of amyloidoses differ significantly in terms of the tissue localization of deposits and for major pathological features.Considering how the amyloidogenesis of the β2-microglobulin mechanism has been scrutinized in depth for the last three decades, the comparative analysis of molecular and pathological properties of wild type β2-microglobulin and of the D76N variant offers a unique opportunity to critically reconsider the current understanding of the relation between the protein's structural properties and its pathologic behavior.
Affiliation: From the Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy and.Show MeSH
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Mentions: We hypothesize that, in the extracellular matrix in the very thin fluid space at the interface between hydrophobic surfaces and the interstitial fluid, the amyloidogenic proteins could partially unfold and expose normally buried hydrophobic patches. These partially folded conformers could locally accumulate and reach a condition of supersaturation (Fig. 3). Such a state is extremely unstable, and several events can break solubility, leading to protein precipitation. Although the shear flow of the fluid is not per se sufficient to unfold globular proteins, it may play a fundamental role in breaking the condition of supersaturation. In fact, in conditions of supersaturation, the intensity of shear flow inversely correlates to the lag phase of β2-m fibrillogenesis (45). All these data suggest that the concentration of β2-m and its level of thermodynamic stability could direct the amyloid formation in two distinct tissue targets. In conditions of high concentration, but relatively good thermodynamic stability, the amyloid is deposited in bones and ligament. When plasma concentration is low, implying a negligible accumulation of β2-m on the collagen surface, bones and ligaments are spared. If a mutation reduces the stability of β2-m (i.e. D76N mutation), the shear stress in the extracellular matrix of visceral organs such as liver, spleen, kidney, and heart is sufficient to unfold the unstable variant and prime a cascade of events as represented in Fig. 3. It is worth noting that the amyloid deposits of patients heterozygous for the mutation D76N do not contain the WT β2-m. However, in vitro, once D76N fibrils are formed, shear stress, generated by the dynamics of a physiologic fluid and the exposure to hydrophobic surface of biological molecules, can also prime amyloidogenesis of WT β2-m (40). These findings are apparently incompatible, but let us grasp the complexity of amyloidogenesis in vivo. The demonstration that, in the presence of a generic extracellular chaperone such as αB crystallin, even in a very low molar ratio, the WT β2-m becomes resistant to the fibrillar conversion induced by the D76N fibrils (40) suggests that in vivo factors such as chaperones can modulate the amyloidogenesis of WT proteins.
Affiliation: From the Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy and.