7opl
CryoEM structure of DNA Polymerase alpha - primase bound to SARS CoV nsp1CryoEM structure of DNA Polymerase alpha - primase bound to SARS CoV nsp1
Structural highlights
FunctionDPOLA_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 PubMedThe molecular mechanisms that drive the infection by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-the causative agent of coronavirus disease 2019 (COVID-19)-are under intense current scrutiny to understand how the virus operates and to uncover ways in which the disease can be prevented or alleviated. Recent proteomic screens of the interactions between viral and host proteins have identified the human proteins targeted by SARS-CoV-2. The DNA polymerase alpha (Pol alpha)-primase complex or primosome-responsible for initiating DNA synthesis during genomic duplication-was identified as a target of nonstructural protein 1 (nsp1), a major virulence factor in the SARS-CoV-2 infection. Here, we validate the published reports of the interaction of nsp1 with the primosome by demonstrating direct binding with purified recombinant components and providing a biochemical characterization of their interaction. Furthermore, we provide a structural basis for the interaction by elucidating the cryo-electron microscopy structure of nsp1 bound to the primosome. Our findings provide biochemical evidence for the reported targeting of Pol alpha by the virulence factor nsp1 and suggest that SARS-CoV-2 interferes with Pol alpha's putative role in the immune response during the viral infection. Structural basis for the interaction of SARS-CoV-2 virulence factor nsp1 with DNA polymerase alpha-primase.,Kilkenny ML, Veale CE, Guppy A, Hardwick SW, Chirgadze DY, Rzechorzek NJ, Maman JD, Pellegrini L Protein Sci. 2022 Feb;31(2):333-344. doi: 10.1002/pro.4220. Epub 2021 Nov 12. PMID:34719824[2] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
|
| ||||||||||||||||||