Abstract
Bloom syndrome is a rare genetic disorder characterized by genomic instability and cancer predisposition. The disease is caused by mutations of the Bloom syndrome protein (BLM). Here we report the crystal structure of a RecQ C-terminal (RQC) domain from human BLM. The structure reveals three novel features of BLM RQC which distinguish it from the previous structures of the Werner syndrome protein (WRN) and RECQ1. First, BLM RQC lacks an aromatic residue at the tip of the β-wing, a key element of the RecQ-family helicases used for DNA-strand separation. Second, a BLM-specific insertion between the N-terminal helices exhibits a looping-out structure that extends at right angles to the β-wing. Deletion mutagenesis of this insertion interfered with binding to Holliday junction. Third, the C-terminal region of BLM RQC adopts an extended structure running along the domain surface, which may facilitate the spatial positioning of an HRDC domain in the full-length protein.
Highlights
Structural Biology Laboratory, Graduate School of Biological Sciences, Nara Institute of Science and Technology, 8916-5 Takayama, Ikoma, Nara 630-0192, Japan
Bloom syndrome protein (BLM) RecQ C-terminal (RQC) lacks an aromatic residue at the tip of the b-wing, a key element of the RecQ-family helicases used for DNA-strand separation
The structure revealed that the helicase-and-ribonuclease D-C-terminal (HRDC) fold of BLM starts at a.a. 1208, limiting the C terminus of the RQC domain to a more N-terminal amino acid
Summary
The structure reveals three novel features of BLM RQC which distinguish it from the previous structures of the Werner syndrome protein (WRN) and RECQ1. A BLM-specific insertion between the N-terminal helices exhibits a looping-out structure that extends at right angles to the b-wing Deletion mutagenesis of this insertion interfered with binding to Holliday junction. Mutations in BLM and WRN are associated with the rare genetic diseases Bloom and Werner syndromes, respectively. BLM and WRN share two conserved regions at the C terminus, referred to as the RecQ C-terminal (RQC) and helicase-and-ribonuclease D-C-terminal (HRDC) domains. It is likely that the variability in RQC sequences yields structural and functional differences between BLM and WRN and contributes to the onset of Bloom and Werner syndromes. The structure and our subsequent biochemical analyses of the domain suggest a mechanism whereby the BLM RQC domain (and the BLM HRDC domain) catalyzes branch migration of a Holliday junction (HJ)
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
