Crystal structure of the Human Pol α B subunit in complex with the C-terminal domain of the catalytic subunit

Yoshiaki Suwa, Jianyou Gu, Andrey G. Baranovskiy, Nigar D. Babayeva, Youri I. Pavlov, Tahir H. Tahirov

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Abstract

In eukaryotic DNA replication, short RNA-DNA hybrid primers synthesized by primase-DNA polymerase α (Prim-Pol α) are needed to start DNA replication by the replicative DNA polymerases, Pol S and Pol e. The C terminus of the Pol α catalytic subunit (p180C) in complex with the B subunit (p70) regulates the RNA priming and DNA polymerizing activities of Prim-Pol α. It tethers Pol α and primase, facilitating RNA primer handover from primase to Pol α. To understand these regulatory mechanisms and to reveal the details of human Pol α organization, we determined the crystal structure of p70 in complex with p180C. The structured portion of p70 includes a phosphodiesterase (PDE) domain and an oligonucleotide/oligosaccharide binding (OB) domain. The N-terminal domain and the linker connecting it to the PDE domain are disordered in the reported crystal structure. The p180C adopts an elongated asymmetric saddle shape, with a three-helix bundle in the middle and zinc-binding modules (Zn1 and Zn2) on each side. The extensive p180C-p70 interactions involve 20 hydrogen bonds and a number of hydrophobic interactions resulting in an extended buried surface of 4080 å2. Importantly, in the structure of the p180C-p70 complex with full-length p70, the residues from the N-terminal to the OB domain contribute to interactions with p180C. The comparative structural analysis revealed both the conserved features and the differences between the human and yeast Pol α complexes.

Original languageEnglish (US)
Pages (from-to)14328-14337
Number of pages10
JournalJournal of Biological Chemistry
Volume290
Issue number23
DOIs
StatePublished - Jun 5 2015

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ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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