PXD039682
PXD039682 is an original dataset announced via ProteomeXchange.
Dataset Summary
Title | Role of Complementarity-Determining Regions 1 and 3 in Pathologic Amyloid Formation by Human Immunoglobulin κ1 Light Chains |
Description | Immunoglobulin 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. |
HostingRepository | PRIDE |
AnnounceDate | 2024-10-22 |
AnnouncementXML | Submission_2024-10-22_05:45:50.847.xml |
DigitalObjectIdentifier | |
ReviewLevel | Peer-reviewed dataset |
DatasetOrigin | Original dataset |
RepositorySupport | Unsupported dataset by repository |
PrimarySubmitter | John R. Engen |
SpeciesList | scientific name: Homo sapiens (Human); NCBI TaxID: 9606; |
ModificationList | No PTMs are included in the dataset |
Instrument | Synapt MS |
Dataset History
Revision | Datetime | Status | ChangeLog Entry |
---|---|---|---|
0 | 2023-01-26 02:31:24 | ID requested | |
1 | 2023-05-23 06:11:12 | announced | |
2 | 2023-11-14 08:48:21 | announced | 2023-11-14: Updated project metadata. |
⏵ 3 | 2024-10-22 05:45:51 | announced | 2024-10-22: 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 affiliation | Department of Chemistry & Chemical Biology, Northeastern University |
contact email | j.engen@northeastern.edu |
lab head | |
John R. Engen | |
contact affiliation | Northeastern University |
contact email | j.engen@northeastern.edu |
dataset submitter |
Full Dataset Link List
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PRIDE project URI |
Repository Record List
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