Thermodynamic and fibril formation studies of full length immunoglobulin light chain AL-09 and its germline protein using scan rate dependent thermal unfolding.
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.
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States.
Luis M
LM
Blancas-Mejía
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States; Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Twin Cities, United States.
Timothy J
TJ
Horn
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States.
Marta
M
Marin-Argany
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States; Division of Hematology, Mayo Clinic, United States.
Matthew
M
Auton
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States; Division of Hematology, Mayo Clinic, United States.
Alexander
A
Tischer
Department of Biochemistry and Molecular Biology, Mayo Clinic, United States; Department of Immunology, Mayo Clinic, United States. Electronic address: ramirezalvarado.marina@mayo.edu.
Marina
M
Ramirez-Alvarado
D002942:Circular Dichroism; D006863:Hydrogen-Ion Concentration; D007147:Immunoglobulin Light Chains / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008854:Microscopy, Electron; D058767:Protein Unfolding; D013056:Spectrophotometry, Ultraviolet; D013696:Temperature; D013816:Thermodynamics
D007147:Immunoglobulin Light Chains
Amyloid fibril formation; Irreversible thermal unfolding; Kinetic stability; Light chain amyloidosis; Protein aggregation