PXD055570

PXD055570 is an original dataset announced via ProteomeXchange.

Title	Conformational differences in the light chain constant domain of immunoglobulin G and free light chain may influence proteolysis in AL amyloidosis
Description	Immunoglobulin light chain amyloidosis (AL) is a life-threatening disease caused by the deposition of monoclonal light chain (LC) and its fragments containing variable (VL) and portions of constant (CL) domains. AL patients feature either monoclonal free LCs circulating as covalent and noncovalent homodimers, or monoclonal immunoglobulin (Ig) wherein LC and heavy chain (HC) form disulfide-linked heterodimers, or both. The role of monoclonal Ig in AL amyloidosis is unclear as prior studies focused on full-length free LC or VL domain. We used a mammalian cell-based expression system to generate four AL patient-derived full-length IgGs, two non-AL IgG controls, and six corresponding free LC proteins derived from IGLV6-57 germline precursor. Comparison of proteins’ secondary structure, thermal stability, proteolytic susceptibility, and disulfide link reduction suggested the importance of local vs. global conformational stability. Analysis of IgGs vs. corresponding free LCs using hydrogen-deuterium exchange mass spectrometry revealed major differences in the local conformation/dynamics of CL domain. In all IgGs vs. LCs, segment containing ß-strand and -helix ßAC-ACBC was more dynamic/exposed while segment ßDC-ßEC was less dynamic/exposed. Notably, these segments overlapped proteolysis-prone regions whose in vivo cleavage generates LC fragments found in AL deposits. Altogether, the results suggest that preferential cleavage in segments ßAC-ACBC of free LC or ßDC-ßEC of IgG helps generate amyloid protein precursors. We propose that protecting these segments using small-molecule stabilizers, which bind to the interfacial cavities CL-CL in free LC or CL-CH1 in IgG, is a potential therapeutic strategy to complement current approaches targeting VL-VL or VL-CL stabilization.
HostingRepository	PRIDE
AnnounceDate	2025-12-08
AnnouncementXML	Submission_2025-12-07_21:56:53.627.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Thomas Wales
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: NEWT:9606;
ModificationList	acetylated residue
Instrument	Synapt MS

Revision	Datetime	Status	ChangeLog Entry
0	2024-09-04 19:26:00	ID requested
⏵ 1	2025-12-07 21:56:54	announced

Klimtchuk ES, Prokaeva T, Spencer BH, Wong S, Ghosh S, Urdaneta A, Morgan G, Wales TE, Gursky O, Conformational Differences in the Light Chain Constant Domain of Immunoglobulin G and Free Light Chain May Influence Proteolysis in AL Amyloidosis. J Mol Biol, 436(23):168837(2024) [pubmed]

10.1016/j.jmb.2024.168837;

submitter keyword: IgG

Amyloid light chain HDX-MS

AL amyloidosis

hydrogen/deuterium exchange mass spectrometry

Thomas E. Wales
contact affiliation	Northeastern University
contact email	t.wales@northeastern.edu
lab head
Thomas Wales
contact affiliation	Northeastern University
contact email	t.wales@northeastern.edu
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD055570
     1. Label: PRIDE project
     2. Name: Conformational differences in the light chain constant domain of immunoglobulin G and free light chain may influence proteolysis in AL amyloidosis