TY - JOUR
T1 - Glycosaminoglycans promote fibril formation by amyloidogenic immunoglobulin light chains through a transient interaction
AU - Martin, Douglas J.
AU - Ramirez-Alvarado, Marina
N1 - Funding Information:
We gratefully acknowledge Dr. William Kirk for technical assistance with ITC. Funding provided by NIH GM071514 (MRA), AHA SDG0630077N (MRA), and NIH F30DK082169 (DJM). We would also like to acknowledge members of the Ramirez–Alvarado lab for the review of this manuscript.
PY - 2011/9
Y1 - 2011/9
N2 - Amyloid formation occurs when a precursor protein misfolds and aggregates, forming a fibril nucleus that serves as a template for fibril growth. Glycosaminoglycans are highly charged polymers known to associate with tissue amyloid deposits that have been shown to accelerate amyloidogenesis in vitro. We studied two immunoglobulin light chain variable domains from light chain amyloidosis patients with 90% sequence identity, analyzing their fibril formation kinetics and binding properties with different glycosaminoglycan molecules. We find that the less amyloidogenic of the proteins shows a weak dependence on glycosaminoglycan size and charge, while the more amyloidogenic protein responds only minimally to changes in the glycosaminoglycan. These glycosaminoglycan effects on fibril formation do not depend on a stable interaction between the two species but still show characteristic traits of an interaction-dependent mechanism. We propose that transient, predominantly electrostatic interactions between glycosaminoglycans and the precursor proteins mediate the acceleration of fibril formation in vitro.
AB - Amyloid formation occurs when a precursor protein misfolds and aggregates, forming a fibril nucleus that serves as a template for fibril growth. Glycosaminoglycans are highly charged polymers known to associate with tissue amyloid deposits that have been shown to accelerate amyloidogenesis in vitro. We studied two immunoglobulin light chain variable domains from light chain amyloidosis patients with 90% sequence identity, analyzing their fibril formation kinetics and binding properties with different glycosaminoglycan molecules. We find that the less amyloidogenic of the proteins shows a weak dependence on glycosaminoglycan size and charge, while the more amyloidogenic protein responds only minimally to changes in the glycosaminoglycan. These glycosaminoglycan effects on fibril formation do not depend on a stable interaction between the two species but still show characteristic traits of an interaction-dependent mechanism. We propose that transient, predominantly electrostatic interactions between glycosaminoglycans and the precursor proteins mediate the acceleration of fibril formation in vitro.
KW - Amyloid
KW - Binding
KW - Kinetics
KW - Light chain amyloidosis
KW - Mechanism
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U2 - 10.1016/j.bpc.2011.05.011
DO - 10.1016/j.bpc.2011.05.011
M3 - Article
C2 - 21640469
AN - SCOPUS:79960193042
SN - 0301-4622
VL - 158
SP - 81
EP - 89
JO - Biophysical Chemistry
JF - Biophysical Chemistry
IS - 1
ER -