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PreprintCited by 4Amyloidosis: Diagnosis, Treatment, OutcomesProtein Structure and DynamicsMultiple Myeloma Research and Treatments

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A conformational fingerprint for amyloidogenic light chains

Open access
Paissoni, Cristina, Puri, Sarita, Broggini, Luca, Sriramoju, Manoj K., Maritan, Martina, Russo, Rosaria, Speranzini, Valentina, Ballabio, Federico, Nuvolone, Mario, Merlini, Giampaolo, Palladini, Giovanni, Hsu, Shang-Te Danny, Ricagno, Stefano, Camilloni, Carlo·2024·eLife
DOI 10.1101/2024.07.12.603200

Preprint — published as 10.7554/elife.102002

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Abstract

Immunoglobulin light chain amyloidosis (AL) and multiple myeloma (MM) both share the overproduction of a clonal light chain (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 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 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 (MD) 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 (HDX-MS) experimentally validated this H state. These findings reconcile diverse experimental observations and provide a precise structural target for future drug design efforts.

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Metadata

Authors
Paissoni, C., Puri, S., Broggini, L., Sriramoju, M. K., Maritan, M., Russo, R., Speranzini, V., Ballabio, F., Nuvolone, M., Merlini, G., Palladini, G., Hsu, S.-T. D., Ricagno, S., & Camilloni, C.
Affiliations
  • University of Milan (IT)
  • IRCCS Policlinico San Donato (IT)
  • Institute of Biological Chemistry, Academia Sinica (TW)
  • University of Pavia (IT)
Corresponding author
Camilloni, Carlo
ORCID
Venue
eLife
Publisher
openRxiv
Published
2024-07-13
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.1101/2024.07.12.603200
OpenAlex
W4400603335
Cited by
4
References
1
Citations by year
2026: 2 · 2024: 2
FWCI
0.60
Type
journal article
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by)
Funders
  • Fondazione AIRC per la ricerca sul cancro ETS (IG 2024 ID 30307)
  • Academia Sinica (AS-CDA-109-L08, AS-IV-114-L04)
  • Fondazione Cariplo (Telethon GJC23044)
  • Ministero della Salute (GR‐2018‐12 368 387)
  • National Science and Technology Council (110-2113-M-001-050-MY3, 113-2123-M-001-010-, 113-2811-M-001-110)
  • Ministero dell'Università e della Ricerca (PRIN 20207XLJB2)
Topics
  • Health Sciences › Medicine › Internal Medicine › Amyloidosis: Diagnosis, Treatment, Outcomes
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
  • Health Sciences › Medicine › Hematology › Multiple Myeloma Research and Treatments
Keywords
immunoglobulin light chain amyloidosis, multiple myeloma, amyloid fibrils, conformational dynamics, conformational ensembles, hydrogen-deuterium exchange, radius of gyration, solvent accessibility, small-angle X-ray scattering, molecular dynamics simulation, drug design targets

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