PDBsum entry 5e0u

DNA binding protein

PDB id: 5e0u

Contents

Protein chains

255 a.a.

18 a.a.

19 a.a.

Waters ×701

PDB id:

5e0u

Name:

DNA binding protein

Title:

Human pcna variant (s228i) complexed with p21 at 1.9 angstroms

Structure:

Proliferating cell nuclear antigen. Chain: a, b, c. Synonym: pcna,cyclin. Engineered: yes. Mutation: yes. Cyclin-dependent kinase inhibitor 1. Chain: d, e, f. Synonym: cdk-interacting protein 1,melanoma differentiation- associated protein 6,mda-6,p21.

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: pcna. Expressed in: escherichia coli. Expression_system_taxid: 562. Synthetic: yes. Organism_taxid: 9606

Resolution:

1.93Å R-factor: 0.170 R-free: 0.221

Authors:

C.M.Duffy,B.J.Hilbert,B.A.Kelch

Key ref:

C.M.Duffy et al. (2016). A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site. J Mol Biol, 428, 1023-1040. PubMed id: 26688547 DOI: 10.1016/j.jmb.2015.11.029

Date:

29-Sep-15 Release date: 20-Apr-16

Protein chains

P12004  (PCNA_HUMAN) -  Proliferating cell nuclear antigen from Homo sapiens

Seq: 261 a.a.

Struc: 255 a.a.*

Protein chains

P38936  (CDN1A_HUMAN) -  Cyclin-dependent kinase inhibitor 1 from Homo sapiens

Seq: 164 a.a.

Struc: 18 a.a.

Protein chain

P38936  (CDN1A_HUMAN) -  Cyclin-dependent kinase inhibitor 1 from Homo sapiens

Seq: 164 a.a.

Struc: 19 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

Enzyme reactions

• Enzyme class: Chains A, B, C, D, E, F: E.C.?

DOI no: 10.1016/j.jmb.2015.11.029

J Mol Biol 428:1023-1040 (2016)

PubMed id: 26688547

A Disease-Causing Variant in PCNA Disrupts a Promiscuous Protein Binding Site.

C.M.Duffy, B.J.Hilbert, B.A.Kelch.

ABSTRACT

The eukaryotic DNA polymerase sliding clamp, proliferating cell nuclear antigen or PCNA, is a ring-shaped protein complex that surrounds DNA to act as a sliding platform for increasing processivity of cellular replicases and for coordinating various cellular pathways with DNA replication. A single point mutation, Ser228Ile, in the human PCNA gene was recently identified to cause a disease whose symptoms resemble those of DNA damage and repair disorders. The mutation lies near the binding site for most PCNA-interacting proteins. However, the structural consequences of the S228I mutation are unknown. Here, we describe the structure of the disease-causing variant, which reveals a large conformational change that dramatically transforms the binding pocket for PCNA client proteins. We show that the mutation markedly alters the binding energetics for some client proteins, while another, p21(CIP1), is only mildly affected. Structures of the disease variant bound to peptides derived from two PCNA partner proteins reveal that the binding pocket can adjust conformation to accommodate some ligands, indicating that the binding site is dynamic and pliable. Our work has implications for the plasticity of the binding site in PCNA and reveals how a disease mutation selectively alters interactions to a promiscuous binding site that is critical for DNA metabolism.