Human beta two microglobulin: Difference between revisions
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Fig.3. summary of hydrophobic side chain differences resulting from a ''trans'' backbone at position 32 | Fig.3. summary of hydrophobic side chain differences resulting from a ''trans'' backbone at position 32 | ||
=== | ===Fibrillar architecture=== | ||
In aqueous solution at neutral or acidic condition, amyloid-like fibrils are formed from b2m that show a long-straight, left-hand twisted and unbranched morphology when observed by EM and AFM (Fig.4) | In aqueous solution at neutral or acidic condition, amyloid-like fibrils are formed from b2m that show a long-straight, left-hand twisted and unbranched morphology when observed by EM and AFM (Fig.4) | ||
[[Image:Fibrillar architecture neutral.png]] [[Image:Acidic.png]] | [[Image:Fibrillar architecture neutral.png]] [[Image:Acidic.png]] | ||
Fig.4. Comparison of experimental data for fibrils of b2m formed at pH 7.0(a) and 2.5(b). EM scale bar indicates 100 nm | Fig.4. Comparison of experimental data for fibrils of b2m formed at pH 7.0(a) and 2.5(b). EM scale bar indicates 100 nm | ||
===A unifying mechanism of b2m fibril formation=== | |||
One of the most striking observations of the b2m assembly pathways is that the fibrils formed commencing from a highly | |||
denatured state or a native-like precursor are apparently indistinguishable, suggesting that their assembly pathways must converge | |||
to a similar fibrillar product. This could occur by unfolding of native b2m to allow reorganisation of the protein structure; or by | |||
refolding of the highly dynamic polypeptide chain at pH 2.5 to a more structurally ordered intermediate species (Fig.5). | |||
[[Image:Unifying mechanism.png]] | |||
Fig.5. Scheme for convergence of the mechanisms of fibril formation at pH 2.5 and 7.0. Regions with high amyloidogenic propensity are displayed in pink. It is not known precisely how oligomers stack or whether they have ordered b-sheet, however, increased intermolecular protein–protein interactions (red) may be important in the reaction pathway. | |||
Similarities between the assembly mechanisms are supported by several reasons. | |||
1. the proposal that aromatic interactions are crucial for driving fibrillogenesis under both sets of conditions. | |||
2. Another convergent feature arises from a suggested model for the fibrils formed at neutral pH that contains a highly charged surface, which could be neutralised at low pH, perhaps allowing for a convergence of the mechanisms of assembly at acidic and neutral pH and explaining why the kinetics of fibril formation are much more rapid under acidic conditions. | |||
3.An additional common characteristic is that many variants capable of fibril formation at neutral pH have the effect of destabilising the Nterminal region of the protein, which is also highly unfolded in the structural ensembles formed at low pH. | |||
4. The role of trans Pro32 in fibril formation at low pH is currently unknown, although 80% of the molecules would be expected to contain the trans conformation in the acid denatured state. Moreover, the observation that the rate of fibril formation of P32G is similar to that of wild-type b2m when studied at pH 2.5 is suggestive of a common trans amyloid precursor. | |||
