Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability

Anastasija Kulik, Klaudia Maruszczak, Dana Thomas, Naomi Nabi, Martin Carr, Richard Bingham, Christopher Cooper

Research output: Contribution to journalArticlepeer-review

Abstract

Polymerase δ-interacting protein 2 (POLDIP2, PDIP38) is a multifaceted, ‘moonlighting’ protein, involved in binding protein partners from many different cellular processes, including mitochondrial metabolism and DNA replication and repair. How POLDIP2 interacts with many different proteins is unknown. Towards this goal, we present the crystal structure of POLDIP2 to 2.8 Å, which exhibited a compact two-domain β-strand-rich globular structure, confirmed by circular dichroism and small angle X-ray scattering approaches. POLDIP2 comprised
canonical DUF525 and YccV domains, but with a conserved domain linker packed tightly, resulting in an ‘extended’ YccV module. A central channel was observed, which we hypothesise could influence structural changes potentially mediated by redox conditions, following observation of a modified cysteine residue in the channel. Unstructured regions were rebuilt by ab initio modelling to generate a model of full-length POLDIP2. Molecular dynamics simulations revealed a highly dynamic N-terminal region tethered to the YccV-domain by an extended linker, potentially facilitating interactions with distal binding partners. Models of
POLDIP2 complexed with two of its partners, PrimPol and PCNA, indicated that dynamic flexibility of the POLDIP2 N-terminus and loop regions likely mediate protein interactions.
Original languageEnglish
JournalProtein Science
Early online date21 Apr 2021
DOIs
Publication statusE-pub ahead of print - 21 Apr 2021

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