From chance to frequent encounters: origins of beta2-microglobulin fibrillogenesis.
It is generally accepted that amyloid formation requires partial, but not complete unfolding of a polypeptide chain. Amyloid formation by beta-2 microglobulin (beta2m), however, readily occurs under strongly native conditions provided that there is exposure to specific transition metal cations. In this review, we discuss transition metal catalyzed conformational changes in several amyloidogenic systems including prion protein, Alzheimer's and Parkinson's diseases. For some systems, including beta2m from dialysis related amyloidosis (DRA), catalysis overcomes an entropic barrier to protein aggregation. Recent data suggest that beta2m samples conformations that are under thermodynamic control, resulting in local or partial unfolding under native conditions. Furthermore, exposure to transition metal cations stabilizes these partially unfolded states and promotes the formation of small oligomers, whose structures are simultaneously near-native and amyloid-like. By serving as a tether, Cu(2+) enables the encounter of amyloidogenic conformations to occur on time scales which are significantly more rapid than would occur between freely diffusing monomeric protein. Once amyloid formation occurs, the requirement for Cu(2+) is lost. We assert that beta2m amyloid fiber formation at neutral pH may be facilitated by rearrangements catalyzed by the transient and pair wise tethering of beta2m at the blood/dialysate interface present during therapeutic hemodialysis.
Eakin
Catherine M
CM
Department of Molecular Biophysics and Biochemistry Yale University, 260 Whitney Avenue, New Haven, CT 06520-8114, USA.
Miranker
Andrew D
AD
D000682:Amyloid / Q000096:biosynthesis*; D000686:Amyloidosis / Q000209:etiology; D002413:Cations, Divalent / Q000494:pharmacology*; D003300:Copper / Q000494:pharmacology; D006801:Humans; D011487:Protein Conformation / Q000187:drug effects; D017510:Protein Folding; D006435:Renal Dialysis / Q000009:adverse effects; D001613:beta 2-Microglobulin / Q000737:chemistry / Q000378:metabolism*
D000682:Amyloid; D002413:Cations, Divalent; D001613:beta 2-Microglobulin; D003300:Copper