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.
Department of Molecular Biophysics and Biochemistry, Yale University, New Haven, CT 06520-8114, USA.
Matthew F
MF
Calabrese
Andrew D
AD
Miranker
D000686:Amyloidosis; D003300:Copper / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D058225:Plaque, Amyloid / Q000737:chemistry / Q000378:metabolism; D011328:Prions / Q000737:chemistry / Q000378:metabolism; D011485:Protein Binding; D017510:Protein Folding; D055503:Protein Multimerization; D006435:Renal Dialysis / Q000009:adverse effects; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism
D011328:Prions; D001613:beta 2-Microglobulin; D003300:Copper