TY - JOUR
T1 - A beta2-microglobulin cleavage variant fibrillates at near-physiological pH
AU - Corlin, Dorthe B
AU - Johnsen, Christina K
AU - Nissen, Mogens H
AU - Heegaard, Niels H H
N1 - Keywords: Acids; Amyloid; Arthritis; Humans; Hydrogen-Ion Concentration; Joints; Protein Stability; beta 2-Microglobulin
PY - 2009
Y1 - 2009
N2 - Beta2-microglobulin (beta2m) deposits as amyloid in dialysis-related amyloidosis (DRA), predominantly in joints. The molecular mechanisms underlying the amyloidogenicity of beta2m are still largely unknown. In vitro, acidic conditions, pH < 4.5, induce amyloid fibrillation of native beta2m within several days. Here, we show that amyloid fibrils are generated in less than an hour when a cleavage variant of beta2m--found in the circulation of many dialysis patients--is exposed to pH levels (pH 6.6) occurring in joints during inflammation. Aggregation and fibrillation, including seeding effects with intact, native beta2m were studied by Thioflavin T fluorescence spectroscopy, turbidimetry, capillary electrophoresis, and electron microscopy. We conclude that a biologically relevant variant of beta2m is amyloidogenic at slightly acidic pH. Also, only a very small amount of preformed fibrils of this variant is required to induce fibrillation of native beta2m. This may explain the apparent lack of detectable amounts of the variant beta2m in extracts of amyloid from DRA patients.
AB - Beta2-microglobulin (beta2m) deposits as amyloid in dialysis-related amyloidosis (DRA), predominantly in joints. The molecular mechanisms underlying the amyloidogenicity of beta2m are still largely unknown. In vitro, acidic conditions, pH < 4.5, induce amyloid fibrillation of native beta2m within several days. Here, we show that amyloid fibrils are generated in less than an hour when a cleavage variant of beta2m--found in the circulation of many dialysis patients--is exposed to pH levels (pH 6.6) occurring in joints during inflammation. Aggregation and fibrillation, including seeding effects with intact, native beta2m were studied by Thioflavin T fluorescence spectroscopy, turbidimetry, capillary electrophoresis, and electron microscopy. We conclude that a biologically relevant variant of beta2m is amyloidogenic at slightly acidic pH. Also, only a very small amount of preformed fibrils of this variant is required to induce fibrillation of native beta2m. This may explain the apparent lack of detectable amounts of the variant beta2m in extracts of amyloid from DRA patients.
U2 - 10.1016/j.bbrc.2009.02.041
DO - 10.1016/j.bbrc.2009.02.041
M3 - Journal article
C2 - 19232323
SN - 0006-291X
VL - 381
SP - 187
EP - 191
JO - Biochemical and Biophysical Research Communications
JF - Biochemical and Biophysical Research Communications
IS - 2
ER -