Molecular playground/beta 2 microglobulin

From Proteopedia

1 Beta-2-microglobulin
2 Aggregation Mechanism
3 Elucidating Early Aggregation Events
4 Additional Resources
5 References

Beta-2-microglobulin

Beta-2 microglobulin (β2m) is a structural protein sub-unit of the class I major histocompatibility complex. β2m is composed of 99 amino acids and has a molecular weight of approximately 12 kDa. Structurally, it features a common to immunoglobulin family members ^[1]. In dialysis patients, β2m has the propensity to form amyloid fibrils in a condition known as dialysis-related amyloidosis (DRA). The mechanism of oligomerization and eventual fibrillization are of particular interest to the Vachet Research Group at the University of Massachusetts-Amherst.

Aggregation Mechanism

There are several processes that can cause β2m to aggregate and ultimately form amyloid fibrils. This includes exposure to low pH, cleavage of the first residues from the N-terminus, incubation with collagen, and exposure to elemental copper. In the copper-catalyzed pathway, the process begins with the formation of a homodimer. His31 is a critical residue for cation binding. Dimer formation is initiated when copper binds near the . Copper binding causes structural changes throughout the protein creating two new planes. These planes interact in an antiparallel fashion which forms the basis of the non-covalent .

Soluble dimers then undergo higher order assembly steps to form larger structures. Evidence for the tetramer and hexamer have been measured using a variety of different analytical methods. Formation of these species eventually leads to the formation of proto-fibril nuclei which serve to then elongate into mature insoluble fibrils.

Elucidating Early Aggregation Events

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 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 ^[2].

One hypothesis has emerged that the cis-trans isomerization of Pro32 is critical to the aggregation process. The 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 ^[3]. 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 is minimally perturbed. Indeed, the H31Y mutant has increased stability relative to wild type and has reduced copper binding characteristics ^[4].