Molecular playground/beta 2 microglobulin: Difference between revisions
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There have been several mutants of β2m generated that have been essential in defining some of the early molecular events that ultimately lead to destabilization and ultimately oligomerization. The <scene name='38/389965/H13f_hexamer/1'>H13F</scene> variant of β2m has permitted the structure of the putative hexamer to be solved. However, this mutation apparently precludes the formation of long amyloid fibrils and instead progress to off-pathway oligomers <ref>2</ref>. | There have been several mutants of β2m generated that have been essential in defining some of the early molecular events that ultimately lead to destabilization and ultimately oligomerization. The <scene name='38/389965/H13f_hexamer/1'>H13F</scene> variant of β2m has permitted the structure of the putative hexamer to be solved. However, this mutation apparently precludes the formation of long amyloid fibrils and instead progress to off-pathway oligomers <ref>2</ref>. | ||
One hypothesis has emerged that the cis-trans isomerization of Pro32 is critical to the aggregation process. The <scene name='38/389965/141211_p32a/ | One hypothesis has emerged that the cis-trans isomerization of Pro32 is critical to the aggregation process. The <scene name='38/389965/141211_p32a/3'>P32A</scene> mutant has proved to be useful in this regard. With the Ala in the trans position, copper binding is enhanced 10,000 fold and has similar oligomerization kinetics to that of wild type-β2m. However, the structural effects of the mutation lead to an alternative dimer structure <ref>3</ref>. Seen here as a tetramer, it appears that the oligomer adopts a intermolecular β-sheet structure which is a hallmark of amyloids. | ||
The critical residue for copper binding, H31, has also been investigated. By mutating His31 to a Tyr, the positive charge is neutralized and the local environment should be minimally perturbed. Indeed, the H31Y mutant has increased stability relative to wild type and has reduced copper binding characteristics <ref>4</ref>. | The critical residue for copper binding, H31, has also been investigated. By mutating His31 to a Tyr, the positive charge is neutralized and the local environment should be minimally perturbed. Indeed, the H31Y mutant has increased stability relative to wild type and has reduced copper binding characteristics <ref>4</ref>. | ||
