PXD039049

PXD039049 is an original dataset announced via ProteomeXchange.

Title	Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains
Description	IgG3 is unique among the IgG subclasses due to its extended hinge, allotypic diversity and enhanced effector functions, including highly efficient pathogen neutralization and complement activation. It is also underrepresented as an immunotherapeutic candidate, partly due to a lack of structural information. Here, we use cryoEM to solve structures of antigen-bound IgG3 alone and in complex with complement components. These structures reveal a propensity for IgG3-Fab clustering, which is possible due to the IgG3 specific flexible upper hinge region and may maximize pathogen neutralization by forming high density antibody arrays. IgG3 forms elevated hexameric Fc platforms that extend above the protein corona to maximize binding to receptors and the complement C1 complex, which here adopts a unique protease conformation that may precede C1 activation. Mass spectrometry revealed that C1 deposits C4b directly onto specific IgG3 residues proximal to the Fab domains. Structural analysis shows this to be caused by the height of the C1-IgG3 complex. Together, these data provide the first structural insights into the role of the unique IgG3 extended hinge, which will aid the development and design of upcoming immunotherapeutics based on IgG3.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_09:07:46.409.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Yassene Mohammed
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-22 01:27:05	ID requested
1	2023-10-24 11:33:33	announced
⏵ 2	2023-11-14 09:07:50	announced	2023-11-14: Updated project metadata.

Abendstein L, Dijkstra DJ, Tjokrodirijo RTN, van Veelen PA, Trouw LA, Hensbergen PJ, Sharp TH, Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains. Nat Commun, 14(1):4027(2023) [pubmed]

submitter keyword: IgG, cryoEM, IgG3

Paul J. Hensbergen
contact affiliation	Center for Proteomics and Metabolomics, LUMC, Leiden, The Netherlands
contact email	p.j.hensbergen@lumc.nl
lab head
Yassene Mohammed
contact affiliation	LUMC/UVIC
contact email	y.mohammed@lumc.nl
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2023/10/PXD039049

PRIDE project URI

• PRIDE
  1. PXD039049
     1. Label: PRIDE project
     2. Name: Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains