PXD034602

PXD034602 is an original dataset announced via ProteomeXchange.

Title	PTX3 structure determination using a hybrid cryo-electron microscopy and AlphaFold approach offers insights into ligand binding and complement activation
Description	Pattern recognition molecules (PRMs) form an important part of innate immunity and respond to infection and damage via triggering processes such as inflammation. The pentraxin family of soluble PRMs comprises long and short pentraxins, with the former containing unique N-terminal regions unrelated to other proteins or each other. No high-resolution structural information exists about long pentraxins, unlike the short pentraxins where there is an abundance of both X-ray and cryo-electron microscopy (cryoEM) derived structures. This study presents for the first time a high-resolution structure of the prototypical long pentraxin, PTX3. CryoEM yielded a 2.5 Å map of the C-terminal pentraxin domains that revealed a radically different quaternary structure compared to other pentraxins, comprising a glycosylated D4 symmetrical octameric complex stabilised by an extensive disulfide network. The cryoEM map indicated α-helices that extended N-terminal of the pentraxin domains that were not fully resolved. AlphaFold was used to predict the remaining N-terminal structure of the octameric PTX3 complex, revealing two long tetrameric coiled coils with two hinge regions, which was validated using classification of cryoEM 2D averages. The resulting hybrid cryoEM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and FGF2, as well as rationalisation of previous biochemical data. Given the relevance of PTX3 in conditions ranging from COVID-19 prognosis, cancer progression and female infertility, this structure could be used to inform the understanding and rational design of therapies for these disorders and processes.
HostingRepository	PRIDE
AnnounceDate	2023-11-14
AnnouncementXML	Submission_2023-11-14_07:59:32.638.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD034602
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	Yassene Mohammed
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Orbitrap Fusion Lumos

Revision	Datetime	Status	ChangeLog Entry
0	2022-06-16 03:51:08	ID requested
1	2022-10-13 19:30:32	announced
⏵ 2	2023-11-14 07:59:33	announced	2023-11-14: Updated project metadata.

Noone DP, Dijkstra DJ, van der Klugt TT, van Veelen PA, de Ru AH, Hensbergen PJ, Trouw LA, Sharp TH, PTX3 structure determination using a hybrid cryoelectron microscopy and AlphaFold approach offers insights into ligand binding and complement activation. Proc Natl Acad Sci U S A, 119(33):e2208144119(2022) [pubmed]

10.6019/PXD034602;

submitter keyword: PTX3

Paul J. Hensbergen
contact affiliation	Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA, 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

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PRIDE project URI

• PRIDE
  1. PXD034602
     1. Label: PRIDE project
     2. Name: PTX3 structure determination using a hybrid cryo-electron microscopy and AlphaFold approach offers insights into ligand binding and complement activation