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PXD039682

PXD039682 is an original dataset announced via ProteomeXchange.

Dataset Summary
TitleRole of Complementarity-Determining Regions 1 and 3 in Pathologic Amyloid Formation by Human Immunoglobulin κ1 Light Chains
DescriptionImmunoglobulin light chain (LC) amyloidosis is a life-threatening disease whose understanding and treatment is complicated by vast numbers of patient-specific mutations. To address molecular origins of the disease, we explored 14 patient-derived and engineered proteins related to κ1-family germline genes IGKVLD-33*01 and IGKVLD-39*01. Hydrogen-deuterium exchange mass spectrometry analysis of local conformational dynamics in full-length recombinant LCs and their fragments was integrated with studies of thermal stability, proteolytic susceptibility, amyloid formation, and amyloidogenic sequence propensities using spectroscopic, electron microscopic and bioinformatics tools. The results were mapped on the atomic structures of native and fibrillary proteins. Proteins from two κ1 subfamilies showed unexpected differences. Compared to their germline counterparts, amyloid LC related to IGKVLD-33*01 was less stable and formed amyloid faster, whereas amyloid LC related to IGKVLD-39*01 had similar stability and formed amyloid slower. These and other differences suggest different major factors influencing amyloid formation. In 33*01-related amyloid LC, these factors involved mutation-induced destabilization of the native structure and probable stabilization of amyloid. The atypical behavior of 39*01-related amyloid LC tracked back to increased dynamics/exposure of amyloidogenic segments in βC’V and βEV that could initiate aggregation, combined with decreased dynamics/exposure near the C23-Cys88 disulfide whose rearrangement is rate-limiting to amyloidogenesis. The results suggest distinct amyloidogenic pathways for closely related LCs and point to the antigen-binding regions CDR1 and CDR3, which are linked via the conserved internal disulfide, as key factors in amyloid formation by various LCs.
HostingRepositoryPRIDE
AnnounceDate2024-10-22
AnnouncementXMLSubmission_2024-10-22_05:45:50.847.xml
DigitalObjectIdentifier
ReviewLevelPeer-reviewed dataset
DatasetOriginOriginal dataset
RepositorySupportUnsupported dataset by repository
PrimarySubmitterJohn R. Engen
SpeciesList scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationListNo PTMs are included in the dataset
InstrumentSynapt MS
Dataset History
RevisionDatetimeStatusChangeLog Entry
02023-01-26 02:31:24ID requested
12023-05-23 06:11:12announced
22023-11-14 08:48:21announced2023-11-14: Updated project metadata.
32024-10-22 05:45:51announced2024-10-22: Updated project metadata.
Publication List
10.1080/13506129.2023.2212397;
Klimtchuk ES, Peterle D, Bullitt E, Connors LH, Engen JR, Gursky O, 1 light chains. Amyloid, 30(4):364-378(2023) [pubmed]
Keyword List
submitter keyword: light chain amyloidosis
misfolded states
protein stability
protein dynamics
HDX MS
hydrogen deuterium exchange mass spectrometry
Contact List
John R. Engen
contact affiliationDepartment of Chemistry & Chemical Biology, Northeastern University
contact emailj.engen@northeastern.edu
lab head
John R. Engen
contact affiliationNortheastern University
contact emailj.engen@northeastern.edu
dataset submitter
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Dataset FTP location
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PRIDE project URI
Repository Record List
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