Abstract
Light chain (AL) amyloidosis is a systemic disease characterized by the formation of immunoglobulin light-chain fibrils in critical organs of the body. The light-chain protein AL-09 presents one severe case of cardiac AL amyloidosis, which contains seven mutations in the variable domain (VL) relative to its germline counterpart, κI O18/O8 VL. Three of these mutations are non-conservative—Y87H, N34I, and K42Q—and previous work has shown that they are responsible for significantly reducing the protein’s thermodynamic stability, allowing fibril formation to occur with fast kinetics and across a wide-range of pH conditions. Currently, however, there is extremely limited structural information available which explicitly describes the residues that are involved in supporting the misfolded fibril structure. Here, we assign the site-specific 15N and 13C chemical shifts of the rigid residues of AL-09 VL fibrils by solid-state NMR, reporting on the regions of the protein involved in the fibril as well as the extent of secondary structure.
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Acknowledgments
This research is supported by the University of Illinois (Centennial Scholars Award to C.M.R.), R01-GM071514 (to M.R.A.), the Mayo Foundation, and the generous support of amyloidosis patients and their families. D.W.P. is an American Heart Association Predoctoral Fellow (15PRE25100008). We thank Marcus D. Tuttle and Alexander M. Barclay for help with SSNMR data acquisition and processing.
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Dennis W. Piehl and Luis M. Blancas-Mejía have contributed equally to this work.
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Piehl, D.W., Blancas-Mejía, L.M., Ramirez-Alvarado, M. et al. Solid-state NMR chemical shift assignments for AL-09 VL immunoglobulin light chain fibrils. Biomol NMR Assign 11, 45–50 (2017). https://doi.org/10.1007/s12104-016-9718-3
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DOI: https://doi.org/10.1007/s12104-016-9718-3