4y97 | pdb_00004y97
Crystal Structure of human Pol alpha B-subunit in complex with C-terminal domain of catalytic subunit
Structural highlights
Function[DPOA2_HUMAN] May play an essential role at the early stage of chromosomal DNA replication by coupling the polymerase alpha/primase complex to the cellular replication machinery (By similarity). [DPOLA_HUMAN] Plays an essential role in the initiation of DNA replication. During the S phase of the cell cycle, the DNA polymerase alpha complex (composed of a catalytic subunit POLA1/p180, a regulatory subunit POLA2/p70 and two primase subunits PRIM1/p49 and PRIM2/p58) is recruited to DNA at the replicative forks via direct interactions with MCM10 and WDHD1. The primase subunit of the polymerase alpha complex initiates DNA synthesis by oligomerising short RNA primers on both leading and lagging strands. These primers are initially extended by the polymerase alpha catalytic subunit and subsequently transferred to polymerase delta and polymerase epsilon for processive synthesis on the lagging and leading strand, respectively. The reason this transfer occurs is because the polymerase alpha has limited processivity and lacks intrinsic 3' exonuclease activity for proofreading error, and therefore is not well suited for replicating long complexes.[1] Publication Abstract from PubMedIn eukaryotic DNA replication, short RNA-DNA hybrid primers synthesized by primase-DNA polymerase alpha (Prim-Pol alpha) are needed to start DNA replication by the replicative DNA polymerases, Pol delta and Pol . The C-terminus of the Pol alpha catalytic subunit (p180C) in complex with the B subunit (p70) regulates the RNA-priming and DNA-polymerizing activities of Prim-Pol alpha. It tethers Pol alpha and primase, facilitating RNA primer handover from primase to Pol alpha. In order to understand these regulatory mechanisms and to reveal the details of human Pol alpha 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 (NTD) 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 A2. Importantly, in the structure of the p180C-p70 complex with full-length p70, the residues from the N-terminal to the OB-fold domain contribute to interactions with p180C. The comparative structural analysis revealed both the conserved features and the differences between the human and yeast Pol alpha complexes. Crystal Structure of the Human Pol alpha B Subunit in Complex with the C-terminal Domain of the Catalytic Subunit.,Suwa Y, Gu J, Baranovskiy AG, Babayeva ND, Pavlov YI, Tahirov TH J Biol Chem. 2015 Apr 6. pii: jbc.M115.649954. PMID:25847248[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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