**Author Listing - Lead/ Submitting Author (we will be communicating with this individual): Name, Institution, City and State where the work was done. Co-authors will be added in a separate section.**
Submitting author: Sarita Puri
Institution: Department of Bioscience, University of Milan, Italy

**Main Body of the Abstract**
Light chain amyloidosis (AL) shares with Multiple Myeloma (MM) the overproduction of a light chain (LC), yet the resulting phenotypes differ, indicating distinct LC involvement. Previously, we performed a comparative analysis of lambda light chains from AL and MM patients, pinpointing proteolysis susceptibility under native conditions as the most distinguishing biophysical parameter. Weber et al. demonstrated in a mouse-derived gamma-LC that even a single amino acid variation in the linker between constant and variable domains leads to heightened conformational dynamics, increased proteolysis susceptibility, and elevated in vitro aggregation propensity. In this study, we aim to delineate a conformational signature that discriminates AL from MM LCs. By subjecting four AL and two MM LCs to in vitro analysis under native conditions using small-angle X-ray scattering (SAXS), we observed that the AL LCs displayed a slightly larger radius of gyration and greater deviation from the experimentally determined structure, indicating enhanced conformational dynamics. Integrating SAXS with molecular dynamics (MD) simulations to generate a conformational ensemble revealed that LCs can adopt multiple states, with variable and constant domains either bent or straight. Specifically, AL LCs favored a distinctive state where both domains had a straight conformation, maximizing solvent accessibility at their relative interfaces. This unique conformation was validated experimentally through hydrogen-deuterium exchange mass spectrometry. Such findings reconcile disparate experimental observations and offer a precise structural target for drug design investigations. Collectively, this study sheds light on the intricate conformational landscape of LCs in AL and provides insights into potential drug design interventions.



Deciphering the conformational landscape of amyloidogenic lambda light chains associated with AL amyloidosis PA29 (#168)

We invite you to attend the XIX International Symposium on Amyloidosis to be held in Rochester, MN.

This symposium is organized as a hybrid meeting (with the focus on in-person) held from Sunday, May 26 through Thursday, May 30, 2024.

Together with the ISA Board and members of Mayo Clinic, a very attractive scientific hybrid program is being planned. The program will cover a variety of types of systemic amyloidosis: ATTR (hereditary and wild-type), AL (light-chain), AA and less frequent forms. There will be key lectures, specific symposia including those company sponsored, oral presentations and poster sessions of accepted abstracts.

COURSE DESCRIPTION
This program will provide a comprehensive review of state-of-the-art education in systemic amyloidosis: basic science, pathophysiology, diagnosis, current and emerging treatments. Scientific presentations will include competitive oral and poster abstracts. The rapid evolution of scientific discovery and expanding treatment options has created tremendous interest in the field and this meeting will fill and important gap in educating scientists and clinicians.