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Systemic amyloidosis: lessons from β2-microglobulin.

Stoppini M, Bellotti V - J. Biol. Chem. (2015)

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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy and.

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Schematic picture of the hypothetical events occurring in the interstitial space where globular soluble proteins undergo fibrillar conversion. The chemical physical characteristics of the interstitial space and forces generated by the fluid flow are well reviewed by Swartz and Fleury (61). Native globular proteins flow through a network of fibrous proteins (i.e. collagen and elastin) and GAGs. These matrix proteins expose hydrophobic patches with which the native globular proteins collide. At the interface between the hydrophobic surface and the aqueous fluid, proteins are exposed to forces sufficient to perturb the folded state. The exposure of normally buried hydrophobic elements further facilitates the interaction with the hydrophobic matrix, local accumulation of partially folded globular conformers reaching a condition of supersaturation. Supersaturation is the precondition for protein aggregation and loss of solubility. Even minimal changes in the intensity of the shear flow can break the very labile soluble state of partially folded proteins when they reach the condition of supersaturation. If supersaturation is not reached, the simple unfolding of the proteins does not imply a fibrillar conversion and the protein can properly refold and escape from the aggregation.
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Figure 3: Schematic picture of the hypothetical events occurring in the interstitial space where globular soluble proteins undergo fibrillar conversion. The chemical physical characteristics of the interstitial space and forces generated by the fluid flow are well reviewed by Swartz and Fleury (61). Native globular proteins flow through a network of fibrous proteins (i.e. collagen and elastin) and GAGs. These matrix proteins expose hydrophobic patches with which the native globular proteins collide. At the interface between the hydrophobic surface and the aqueous fluid, proteins are exposed to forces sufficient to perturb the folded state. The exposure of normally buried hydrophobic elements further facilitates the interaction with the hydrophobic matrix, local accumulation of partially folded globular conformers reaching a condition of supersaturation. Supersaturation is the precondition for protein aggregation and loss of solubility. Even minimal changes in the intensity of the shear flow can break the very labile soluble state of partially folded proteins when they reach the condition of supersaturation. If supersaturation is not reached, the simple unfolding of the proteins does not imply a fibrillar conversion and the protein can properly refold and escape from the aggregation.

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.


Systemic amyloidosis: lessons from β2-microglobulin.

Stoppini M, Bellotti V - J. Biol. Chem. (2015)

Schematic picture of the hypothetical events occurring in the interstitial space where globular soluble proteins undergo fibrillar conversion. The chemical physical characteristics of the interstitial space and forces generated by the fluid flow are well reviewed by Swartz and Fleury (61). Native globular proteins flow through a network of fibrous proteins (i.e. collagen and elastin) and GAGs. These matrix proteins expose hydrophobic patches with which the native globular proteins collide. At the interface between the hydrophobic surface and the aqueous fluid, proteins are exposed to forces sufficient to perturb the folded state. The exposure of normally buried hydrophobic elements further facilitates the interaction with the hydrophobic matrix, local accumulation of partially folded globular conformers reaching a condition of supersaturation. Supersaturation is the precondition for protein aggregation and loss of solubility. Even minimal changes in the intensity of the shear flow can break the very labile soluble state of partially folded proteins when they reach the condition of supersaturation. If supersaturation is not reached, the simple unfolding of the proteins does not imply a fibrillar conversion and the protein can properly refold and escape from the aggregation.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4400370&req=5

Figure 3: Schematic picture of the hypothetical events occurring in the interstitial space where globular soluble proteins undergo fibrillar conversion. The chemical physical characteristics of the interstitial space and forces generated by the fluid flow are well reviewed by Swartz and Fleury (61). Native globular proteins flow through a network of fibrous proteins (i.e. collagen and elastin) and GAGs. These matrix proteins expose hydrophobic patches with which the native globular proteins collide. At the interface between the hydrophobic surface and the aqueous fluid, proteins are exposed to forces sufficient to perturb the folded state. The exposure of normally buried hydrophobic elements further facilitates the interaction with the hydrophobic matrix, local accumulation of partially folded globular conformers reaching a condition of supersaturation. Supersaturation is the precondition for protein aggregation and loss of solubility. Even minimal changes in the intensity of the shear flow can break the very labile soluble state of partially folded proteins when they reach the condition of supersaturation. If supersaturation is not reached, the simple unfolding of the proteins does not imply a fibrillar conversion and the protein can properly refold and escape from the aggregation.
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.

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.

View Article: PubMed Central - PubMed

Affiliation: From the Department of Molecular Medicine, Institute of Biochemistry, University of Pavia, 27100 Pavia, Italy and.

Show MeSH
Related in: MedlinePlus