TY - JOUR
T1 - Thermodynamic and fibril formation studies of full length immunoglobulin light chain AL-09 and its germline protein using scan rate dependent thermal unfolding
AU - Blancas-Mejía, Luis M.
AU - Horn, Timothy J.
AU - Marin-Argany, Marta
AU - Auton, Matthew
AU - Tischer, Alexander
AU - Ramirez-Alvarado, Marina
N1 - Funding Information:
This work was supported by National Institutes of Health R01 GM 071514 (MRA). We are also thankful for the financial support offered by Dr. Morie Gertz and the Seidler Professorship , the Mayo Foundation , and the generosity of amyloidosis patients and their families.
Publisher Copyright:
© 2015 Elsevier B.V.
PY - 2015/8/12
Y1 - 2015/8/12
N2 - Abstract Light chain (AL) amyloidosis is a fatal disease where monoclonal immunoglobulin light chains deposit as insoluble amyloid fibrils. For many years it has been considered that AL amyloid deposits are formed primarily by the variable domain, while its constant domain has been considered not to be amyloidogenic. However recent studies identify full length (FL) light chains as part of the amyloid deposits. In this report, we compare the stabilities and amyloidogenic properties of two light chains, an amyloid-associated protein AL-09 FL, and its germline protein κ I O18/O8 FL (IGKV 1-33). We demonstrate that the thermal unfolding for both proteins is irreversible and scan rate dependent, with similar stability parameters compared to their VL counterparts. In addition, the constant domain seems to modulate their amyloidogenic properties and affect the morphology of the amyloid fibrils. These results allow us to understand the role of the kappa constant domain in AL amyloidosis.
AB - Abstract Light chain (AL) amyloidosis is a fatal disease where monoclonal immunoglobulin light chains deposit as insoluble amyloid fibrils. For many years it has been considered that AL amyloid deposits are formed primarily by the variable domain, while its constant domain has been considered not to be amyloidogenic. However recent studies identify full length (FL) light chains as part of the amyloid deposits. In this report, we compare the stabilities and amyloidogenic properties of two light chains, an amyloid-associated protein AL-09 FL, and its germline protein κ I O18/O8 FL (IGKV 1-33). We demonstrate that the thermal unfolding for both proteins is irreversible and scan rate dependent, with similar stability parameters compared to their VL counterparts. In addition, the constant domain seems to modulate their amyloidogenic properties and affect the morphology of the amyloid fibrils. These results allow us to understand the role of the kappa constant domain in AL amyloidosis.
KW - Amyloid fibril formation
KW - Irreversible thermal unfolding
KW - Kinetic stability
KW - Light chain amyloidosis
KW - Protein aggregation
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U2 - 10.1016/j.bpc.2015.07.005
DO - 10.1016/j.bpc.2015.07.005
M3 - Article
C2 - 26263488
AN - SCOPUS:84938858670
VL - 207
SP - 13
EP - 20
JO - Biophysical Chemistry
JF - Biophysical Chemistry
SN - 0301-4622
M1 - 5846
ER -