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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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β2-m structure (Protein Data Bank (PDB) entry 2yxf) highlighting the N-terminal peptide and three key residues: Pro-32, Trp-60, and Asp-76.Exa N-terminal peptide, the six N-terminal residues lacking in ΔN6β2-m.
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Figure 2: β2-m structure (Protein Data Bank (PDB) entry 2yxf) highlighting the N-terminal peptide and three key residues: Pro-32, Trp-60, and Asp-76.Exa N-terminal peptide, the six N-terminal residues lacking in ΔN6β2-m.

Mentions: β2-m, similar to many other globular amyloidogenic proteins, displays a strong propensity to spontaneously aggregate into soluble oligomers; in particular, β2-m does so in the physiologic buffer (26, 28, 33). It is likely that the oligomerization is mainly primed by a small population of partially folded conformers in equilibrium with the fully folded protein. NMR studies, molecular dynamic simulation, capillary electrophoresis, and spectroscopic analysis highlighted the existence of a partially folded intermediate, initially named I2 (34, 35), in which specific regions of the molecule exhibit a very high flexibility and rapid structural fluctuations (36). The fluctuation toward a partially folded state is probably dictated by the peculiar dynamics of the loop interconnecting the strands D and E. This loop is particularly unstable, most likely due to the presence of a tryptophan (Trp-60) in the center of the loop (37, 38) (Fig. 2).


Systemic amyloidosis: lessons from β2-microglobulin.

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

β2-m structure (Protein Data Bank (PDB) entry 2yxf) highlighting the N-terminal peptide and three key residues: Pro-32, Trp-60, and Asp-76.Exa N-terminal peptide, the six N-terminal residues lacking in ΔN6β2-m.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: β2-m structure (Protein Data Bank (PDB) entry 2yxf) highlighting the N-terminal peptide and three key residues: Pro-32, Trp-60, and Asp-76.Exa N-terminal peptide, the six N-terminal residues lacking in ΔN6β2-m.
Mentions: β2-m, similar to many other globular amyloidogenic proteins, displays a strong propensity to spontaneously aggregate into soluble oligomers; in particular, β2-m does so in the physiologic buffer (26, 28, 33). It is likely that the oligomerization is mainly primed by a small population of partially folded conformers in equilibrium with the fully folded protein. NMR studies, molecular dynamic simulation, capillary electrophoresis, and spectroscopic analysis highlighted the existence of a partially folded intermediate, initially named I2 (34, 35), in which specific regions of the molecule exhibit a very high flexibility and rapid structural fluctuations (36). The fluctuation toward a partially folded state is probably dictated by the peculiar dynamics of the loop interconnecting the strands D and E. This loop is particularly unstable, most likely due to the presence of a tryptophan (Trp-60) in the center of the loop (37, 38) (Fig. 2).

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