Proteomics

Dataset Information

0

Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis


ABSTRACT: Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. In vivo, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N- and C-termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N- and C-terminome of the LC proteoforms in fibrils extracted from the hearts of two AL cardiomyopathy patients, using a proteomic approach based on derivatization of N- and C-terminal residues, followed by mapping of fragmentation sites on the structures of native and fibrillar relevant LCs. We provide the first high-specificity map of proteolytic cleavages in natural AL amyloid. Proteolysis occurs both on the LCs’ variable and constant domains, generating a complex fragmentation pattern. The structural analysis indicates extensive remodeling, by multiple proteases, largely taking place on poorly folded regions of the fibril surfaces. This study adds novel important knowledge on amyloid LCs processing: although our data do not exclude that proteolysis of native LC dimers may destabilize their structure and favor fibril formation, they show that LC deposition largely precedes the proteolytic events documentable in mature AL fibrils.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Heart

DISEASE(S): Amyloidosis

SUBMITTER: Giulia Mazzini  

LAB HEAD: Giovanni Palladini

PROVIDER: PXD020858 | Pride | 2020-10-15

REPOSITORIES: Pride

altmetric image

Publications

Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis.

Lavatelli Francesca F   Mazzini Giulia G   Ricagno Stefano S   Iavarone Federica F   Rognoni Paola P   Milani Paolo P   Nuvolone Mario M   Swuec Paolo P   Caminito Serena S   Tasaki Masayoshi M   Chaves-Sanjuan Antonio A   Urbani Andrea A   Merlini Giampaolo G   Palladini Giovanni G  

The Journal of biological chemistry 20200920 49


Amyloid fibrils are polymeric structures originating from aggregation of misfolded proteins. <i>In vivo</i>, proteolysis may modulate amyloidogenesis and fibril stability. In light chain (AL) amyloidosis, fragmented light chains (LCs) are abundant components of amyloid deposits; however, site and timing of proteolysis are debated. Identification of the N and C termini of LC fragments is instrumental to understanding involved processes and enzymes. We investigated the N and C terminome of the LC  ...[more]

Similar Datasets

2021-11-25 | PXD026528 | Pride
2023-05-23 | PXD039682 | Pride
2023-06-29 | MSV000092311 | MassIVE
| E-GEOD-68789 | biostudies-arrayexpress
2017-03-30 | GSE94247 | GEO
2022-08-12 | PXD025185 | Pride
2023-10-30 | PXD045698 | Pride
| E-GEOD-85952 | biostudies-arrayexpress
2014-08-01 | GSE59237 | GEO
| E-GEOD-59237 | biostudies-arrayexpress