Structure of the processive human Pol δ holoenzyme.

Amino Acid Motifs Catalytic Domain Cryoelectron Microscopy DNA / metabolism DNA Polymerase III / chemistry DNA Replication Flap Endonucleases / chemistry Holoenzymes Humans Models, Molecular Proliferating Cell Nuclear Antigen / chemistry Protein Binding Protein Subunits Structure-Activity Relationship

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
28 02 2020
Historique:
received: 17 12 2019
accepted: 07 02 2020
entrez: 1 3 2020
pubmed: 1 3 2020
medline: 27 5 2020
Statut: epublish

Résumé

In eukaryotes, DNA polymerase δ (Pol δ) bound to the proliferating cell nuclear antigen (PCNA) replicates the lagging strand and cooperates with flap endonuclease 1 (FEN1) to process the Okazaki fragments for their ligation. We present the high-resolution cryo-EM structure of the human processive Pol δ-DNA-PCNA complex in the absence and presence of FEN1. Pol δ is anchored to one of the three PCNA monomers through the C-terminal domain of the catalytic subunit. The catalytic core sits on top of PCNA in an open configuration while the regulatory subunits project laterally. This arrangement allows PCNA to thread and stabilize the DNA exiting the catalytic cleft and recruit FEN1 to one unoccupied monomer in a toolbelt fashion. Alternative holoenzyme conformations reveal important functional interactions that maintain PCNA orientation during synthesis. This work sheds light on the structural basis of Pol δ's activity in replicating the human genome.

Identifiants

DOI: 10.1038/s41467-020-14898-6 PMID: 32111820 PMC: PMC7048817
pubmed: 32111820
doi: 10.1038/s41467-020-14898-6
pii: 10.1038/s41467-020-14898-6
pmc: PMC7048817
doi:

Substances chimiques

Holoenzymes 0
PCNA protein, human 0
Proliferating Cell Nuclear Antigen 0
Protein Subunits 0
DNA 9007-49-2
DNA Polymerase III EC 2.7.7.7
Flap Endonucleases EC 3.1.-
FEN1 protein, human EC 3.1.11.-

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

1109

Subventions

Organisme : Medical Research Council
ID : MC_PC_17136
Pays : United Kingdom

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Auteurs

Claudia Lancey (C)

Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Lancaster Rd, Leicester, LE1 7HB, UK.

Muhammad Tehseen (M)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.

Vlad-Stefan Raducanu (VS)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.
ORCID: 0000-0001-6722-9262

Fahad Rashid (F)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.

Nekane Merino (N)

CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800, 48160, Derio, Spain.
ORCID: 0000-0003-0721-4813

Timothy J Ragan (TJ)

Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Lancaster Rd, Leicester, LE1 7HB, UK.
ORCID: 0000-0002-6233-3375

Christos G Savva (CG)

Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Lancaster Rd, Leicester, LE1 7HB, UK.

Manal S Zaher (MS)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.
ORCID: 0000-0002-7785-4384

Afnan Shirbini (A)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia.

Francisco J Blanco (FJ)

CIC bioGUNE, Parque Tecnológico de Bizkaia Edificio 800, 48160, Derio, Spain.
IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
ORCID: 0000-0003-2545-4319

Samir M Hamdan (SM)

Division of Biological and Environmental Sciences and Engineering, King Abdullah University of Science and Technology, Thuwal, 23955, Saudi Arabia. samir.hamdan@kaust.edu.sa.
ORCID: 0000-0001-5192-1852

Alfredo De Biasio (A)

Leicester Institute of Structural & Chemical Biology and Department of Molecular & Cell Biology, University of Leicester, Lancaster Rd, Leicester, LE1 7HB, UK. adb43@leicester.ac.uk.

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Classifications MeSH

questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Structure secondaire des protéines › Motifs d'acides aminés › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Phénomènes chimiques › Phénomènes biochimiques › Conformation moléculaire › Conformation des protéines › Éléments structuraux des protéines › Domaine catalytique › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Techniques d'investigation › Microscopie électronique › Cryomicroscopie électronique › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ADN › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › DNA nucleotidyltransferases › DNA-directed DNA polymerase › DNA polymerase III › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Phénomènes génétiques › Réplication de l'ADN › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Endonucleases › Endodeoxyribonucleases › Flap endonucleases › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Holoenzymes › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Structure of the processive human Pol δ holoenzyme.
questionsmedicales.fr › Techniques d'investigation › Modèles théoriques › Modèles moléculaires › Structure of the processive human Pol δ holoenzyme.
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