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Structure of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability
Structural highlights
FunctionPDIP2_HUMAN Involved in DNA damage tolerance by regulating translesion synthesis (TLS) of templates carrying DNA damage lesions such as 8oxoG and abasic sites (PubMed:24191025). May act by stimulating activity of DNA polymerases involved in TLS, such as PRIMPOL and polymerase delta (POLD1) (PubMed:24191025, PubMed:26984527).[1] [2] Publication Abstract from PubMedPolymerase delta-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 a, which exhibited a compact two-domain beta-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. This article is protected by copyright. All rights reserved. Crystal structure and molecular dynamics of human POLDIP2, a multifaceted adaptor protein in metabolism and genome stability.,Kulik AA, Maruszczak KK, Thomas DC, Nabi NLA, Carr M, Bingham RJ, Cooper CDO Protein Sci. 2021 Apr 21. doi: 10.1002/pro.4085. PMID:33884680[3] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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