Crystal Structure of Entamoeba histolytica Cdc45 Suggests a Conformational Switch that May Regulate DNA Replication

Fredy Kurniawan, Ke Shi, Kayo Kurahashi, Anja Katrin Bielinsky, Hideki Aihara

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Cdc45 plays a critical role at the core of the eukaryotic DNA replisome, serving as an essential scaffolding component of the replicative helicase holoenzyme Cdc45-MCM-GINS (CMG) complex. A 1.66-Å-resolution crystal structure of the full-length Cdc45 protein from Entamoeba histolytica shows a protein fold similar to that observed previously for human Cdc45 in its active conformation, featuring the overall disk-like monomer shape and intimate contacts between the N- and C-terminal DHH domains. However, the E. histolytica Cdc45 structure shows several unique features, including a distinct orientation of the C-terminal DHHA1 domain, concomitant disordering of the adjacent protruding α-helical segment implicated in DNA polymerase ε interactions, and a unique conformation of the GINS/Mcm5-binding loop. These structural observations collectively suggest the possibility that Cdc45 can sample multiple conformations corresponding to different functional states. We propose that such conformational switch of Cdc45 may allow regulation of protein-protein interactions important in DNA replication.
Original languageEnglish (US)
Pages (from-to)102-109
Number of pages8
JournaliScience
Volume3
DOIs
StatePublished - May 25 2018

Bibliographical note

Funding Information:
We thank Surajit Banerjee for assistance in X-ray data collection. This work is based upon research conducted at the Advanced Photon Source (APS) Northeastern Collaborative Access Team beamlines, which are funded by the US National Institutes of Health (NIGMS P41-GM103403 ). The Pilatus 6M detector on 24-ID-C beamline is funded by an NIH-ORIP HEI grant ( S10 RR029205 ). This research used resources of the APS, a US Department of Energy (DOE) Office of Science User Facility operated for the DOE Office of Science by Argonne National Laboratory under Contract No. DE-AC02-06CH11357, and those of the Minnesota Supercomputing Institute. This work was supported by grants from the National Institutes of Health (NIGMS R35-GM118047 to H.A, and R01-GM074917 to A.-K.B.).

Publisher Copyright:
© 2018 The Author(s)

Keywords

  • Biophysics
  • Protein Structure Aspects
  • Structural Biology

PubMed: MeSH publication types

  • Journal Article

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