PXD020858

PXD020858 is an original dataset announced via ProteomeXchange.

Title	Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis
Description	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.
HostingRepository	PRIDE
AnnounceDate	2020-10-15
AnnouncementXML	Submission_2020-10-15_05:50:53.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Giulia Mazzini
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	amidated residue; dimethylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-08-11 17:03:38	ID requested
⏵ 1	2020-10-15 05:50:54	announced

Lavatelli F, Mazzini G, Ricagno S, Iavarone F, Rognoni P, Milani P, Nuvolone M, Swuec P, Caminito S, Tasaki M, Chaves-Sanjuan A, Urbani A, Merlini G, Palladini G, Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis. J Biol Chem, 295(49):16572-16584(2020) [pubmed]

submitter keyword: Proteomics, Amyloid fibrils, Mass Spectrometry, Proteolysis, Cardiomyopathy

Giovanni Palladini
contact affiliation	Amyloidosis Treatment and Research Center, Fondazione IRCCS Policlinico San Matteo and University of Pavia, Italy
contact email	g.palladini@smatteo.pv.it
lab head
Giulia Mazzini
contact affiliation	Fondazione IRCCS Policlinico San Matteo
contact email	g.mazzini@smatteo.pv.it
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020858
     1. Label: PRIDE project
     2. Name: Mass spectrometry characterization of light chain fragmentation sites in cardiac AL amyloidosis: insights into the timing of proteolysis