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Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Shaji K. Kumar, MD
Prashant Kapoor, MD, FACP
Posted: Monday, March 20, 2023
Alexander K. Buell, PhD, of Heinrich-Heine-Universität Düsseldorf, Germany, and colleagues developed a method to investigate the biophysical properties underlying immunoglobulin light chain amyloidogenicity in patients with multiple myeloma. Their findings, which were published in the journal BMC Biology, challenge the current paradigm that its origin is to be found in the amino acid sequence alone.
“[Our novel and systematic workflow] represents probably the most comprehensive and detailed characterization of disease-related immunoglobulin light chains to date,” the investigators commented.
Using their thermodynamic and aggregation fingerprinting approach, the investigators characterized immunoglobulin light chains derived from the urine of nine patients with multiple myeloma. Despite lacking pathologic aggregate formation, the set was found to span the entire range of values in those sequence-related biophysical parameters previously proposed to define in vivo amyloidogenicity, such as dimerization (0.1–1.0), thermal stability (50–64°C), efficiency of refolding (0.0–0.7), and trypsin digestibility (0.1–1.0). All of the samples appeared to demonstrate the ability to form amyloid fibrils in vitro under the influence of proteolytic cleavage by copurified cathepsins.
“We show that in vivo aggregation behavior is unlikely to be mechanistically linked to any single biophysical or biochemical parameter, and amyloidogenic potential is widespread in immunoglobulin light chain sequences and is not confined to those sequences that form amyloid fibrils in patients,” the investigators concluded. “Our findings suggest that protein sequence, environmental conditions, and presence and action of proteases all determine the ability of light chains to form amyloid fibrils in patients.”
Disclosure: The study authors reported no conflicts of interest.
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