PXD026528 is an
original dataset announced via ProteomeXchange.
Dataset Summary
Title | A conservative point mutation in a dynamic antigen-binding loop of human immunoglobulin λ6 light chain promotes pathologic amyloid formation |
Description | Immunoglobulin light chain (LC) amyloidosis (AL) is a life-threatening human disease wherein free monoclonal LCs deposit in vital organs. To determine what makes some LCs amyloidogenic, we explored patient-based amyloidogenic and non-amyloidogenic recombinant LCs from the λ6 subtype prevalent in AL. Hydrogen-deuterium exchange mass spectrometry, structural stability, proteolysis, and amyloid growth studies revealed that the antigen-binding CDR1 loop is the least protected part in the variable domain of λ6 LC, particularly in the AL variant. N32T substitution in CRD1 is identified as a driver of amyloid formation. Substitution N32T increased the amyloidogenic propensity of CDR1 loop, decreased its protection in the native structure, and accelerated amyloid growth in the context of other AL substitutions. The destabilizing effects of N32T propagated across the molecule increasing its dynamics in regions ~30Å away from the substitution site. Such striking long-range effects of a conservative point substitution in a dynamic surface loop may be relevant to Ig function. Comparison of patient-derived and engineered proteins showed that N32T interactions with other substitution sites must contribute to amyloidosis. The results suggest that CDR1 is critical in amyloid formation by other λ6 LCs. |
HostingRepository | PRIDE |
AnnounceDate | 2021-11-25 |
AnnouncementXML | Submission_2021-11-25_07:43:20.436.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 | 2021-06-07 02:45:16 | ID requested | |
⏵ 1 | 2021-11-25 07:43:20 | announced | |
Publication List
Dataset with its publication pending |
Keyword List
submitter keyword: Light chain amyloidosis |
Protein conformation |
Hydrogen-deuterium exchange mass spectrometry |
Propagation of mutational effects |
CDR loops |
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
Dataset FTP location
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PRIDE project URI |
Repository Record List
[ + ]
[ - ]
- PRIDE
- PXD026528
- Label: PRIDE project
- Name: A conservative point mutation in a dynamic antigen-binding loop of human immunoglobulin λ6 light chain promotes pathologic amyloid formation