A conformational fingerprint for amyloidogenic light chains
Both immunoglobulin light-chain (LC) amyloidosis (AL) and multiple myeloma (MM) share the overproduction of a clonal LC. However, while LCs in MM remain soluble in circulation, AL LCs misfold into toxic-soluble species and amyloid fibrils that accumulate in organs, leading to distinct clinical manifestations. The significant sequence variability of LCs has hindered the understanding of the mechanisms driving LC aggregation. Nevertheless, emerging biochemical properties, including dimer stability, conformational dynamics, and proteolysis susceptibility, distinguish AL LCs from those in MM under native conditions. This study aimed to identify a<sup>2</sup> conformational fingerprint distinguishing AL from MM LCs. Using small-angle X-ray scattering (SAXS) under native conditions, we analyzed four AL and two MM LCs. We observed that AL LCs exhibited a slightly larger radius of gyration and greater deviations from X-ray crystallography-determined or predicted structures, reflecting enhanced conformational dynamics. SAXS data, integrated with molecular dynamics simulations, revealed a conformational ensemble where LCs adopt multiple states, with variable and constant domains either bent or straight. AL LCs displayed a distinct, low-populated, straight conformation (termed H state), which maximized solvent accessibility at the interface between constant and variable domains. Hydrogen-deuterium exchange mass spectrometry experimentally validated this H state. These findings reconcile diverse experimental observations and provide a precise structural target for future drug design efforts.
Authors
- Mario Nuvolone (ORCID: https://orcid.org/0000-0001-8334-1684)
- Shang‐Te Danny Hsu (ORCID: https://orcid.org/0000-0002-7231-0185)
- Luca Broggini (ORCID: https://orcid.org/0000-0001-9472-6854)
- Stéfano Ricagno (ORCID: https://orcid.org/0000-0001-6678-5873)
- Rosaria Russo (ORCID: https://orcid.org/0000-0003-0011-5775)
- Carlo Camilloni (ORCID: https://orcid.org/0000-0002-9923-8590)
- Martina Maritan (ORCID: https://orcid.org/0000-0001-9901-1153)
- Valentina Speranzini (ORCID: https://orcid.org/0000-0002-7219-3097)
- Manoj Kumar Sriramoju (ORCID: https://orcid.org/0000-0002-7244-0780)
- Federico Ballabio (ORCID: https://orcid.org/0000-0001-5702-3674)
- Giovanni O. Palladini (ORCID: https://orcid.org/0000-0001-5994-5138)
- Cristina Paissoni (ORCID: https://orcid.org/0000-0002-3101-6705)
- Giampaolo Merlini (ORCID: https://orcid.org/0000-0001-7680-3254)
- Sarita Puri (ORCID: https://orcid.org/0000-0002-0896-9460)
Institutions
- Hiroshima University (JP)
- National Taiwan University (TW)
- Indian Institute of Science Education and Research Pune (IN)
- University of Milan (IT)
- University of Pavia (IT)
- Bioscience (China) (CN)
- Institute of Biological Chemistry, Academia Sinica (TW)
- IRCCS Policlinico San Donato (IT)
- International Institute for Sustainability (BR)
- Policlinico San Matteo Fondazione (IT)
- Istituti di Ricovero e Cura a Carattere Scientifico (IT)
Publication Details
- Journal
- eLife
- Published
- 2024-11-19
- DOI
- https://doi.org/10.7554/elife.102002
- Citations
- 6
- Primary Topic
- Alzheimer's disease research and treatments
- Type
- article
- Field-Weighted Citation Impact
- 1.96
Funders
- Academia Sinica
- Partnership for Advanced Computing in Europe AISBL
- Fondazione Cariplo
- Ministero della Salute
- National Science and Technology Council
- Ministero dell'Università e della Ricerca