PTX3 structure determination using a hybrid cryoelectron microscopy and AlphaFold approach offers insights into ligand binding and complement activation.


Journal

Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876

Informations de publication

Date de publication:
16 08 2022
Historique:
entrez: 8 8 2022
pubmed: 9 8 2022
medline: 11 8 2022
Statut: ppublish

Résumé

Pattern recognition molecules (PRMs) form an important part of innate immunity, where they facilitate the response to infections and damage by 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 complete high-resolution structural information exists about long pentraxins, unlike the short pentraxins, where there is an abundance of both X-ray and cryoelectron microscopy (cryo-EM)-derived structures. This study presents a high-resolution structure of the prototypical long pentraxin, PTX3. Cryo-EM 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 stabilized by an extensive disulfide network. The cryo-EM 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 cryo-EM two-dimensional averages. The resulting hybrid cryo-EM/AlphaFold structure allowed mapping of ligand binding sites, such as C1q and fibroblast growth factor-2, as well as rationalization 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.

Identifiants

pubmed: 35939690
doi: 10.1073/pnas.2208144119
pmc: PMC9388099
doi:

Substances chimiques

Ligands 0
Serum Amyloid P-Component 0
PTX3 protein 148591-49-5
C-Reactive Protein 9007-41-4

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

e2208144119

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Auteurs

Dylan P Noone (DP)

Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Douwe J Dijkstra (DJ)

Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Teun T van der Klugt (TT)

Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

Peter A van Veelen (PA)

Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Arnoud H de Ru (AH)

Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Paul J Hensbergen (PJ)

Center for Proteomics and Metabolomics, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Leendert A Trouw (LA)

Department of Immunology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.

Thomas H Sharp (TH)

Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.

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Classifications MeSH