Metal binding sheds light on mechanisms of amyloid assembly.

Beta-2 microglobulin (beta2m) is the protein responsible for amyloid deposition in Dialysis-Related Amyloidosis (DRA). Aggregation can be induced by various solution conditions including exposure to divalent metal, incubation at acidic pH, and limited proteolysis. Using Cu(2+) as a trigger, we have trapped, isolated, and crystallized a stable oligomer of beta2m that is populated under amyloidogenic solution conditions (Calabrese et al. Nat Struct Mol Biol 2008; 15:965-71). This structure reveals that Cu(2+)-binding is associated with dramatic conformational rearrangements. This has allowed us to postulate a set of structural changes common to all beta2m aggregation pathways. Cu(2+) serves as a potential trigger in other aggregation systems such as Abeta, alpha-synuclein, and mammalian Prion (PrP). A comparison of Cu(2+) binding to beta2m and PrP reveals common features. Therefore, in addition to providing insight into DRA, induction of structure by Cu(2+) binding appears to be a recurring structural motif for pathological changes in conformation.