Metal binding sheds light on mechanisms of amyloid assembly

Abstract

β-2 microglobulin (β2m) 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 Cu2+ as a trigger, we have trapped, isolated, and crystallized a stable oligomer of β2m that is populated under amyloidogenic solution conditions (Calabrese et al. Nat Struct Mol Biol 2008; 15:965-71). This structure reveals that Cu2+-binding is associated with dramatic conformational rearrangements. This has allowed us to postulate a set of structural changes common to all β2m aggregation pathways. Cu2+ serves as a potential trigger in other aggregation systems such as Aβ, α-synuclein, and mammalian Prion (PrP). A comparison of Cu2+ binding to β2m and PrP reveals common features. Therefore, in addition to providing insight into DRA, induction of structure by Cu2+ binding appears to be a recurring structural motif for pathological changes in conformation. ©2009 Landes Bioscience.