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바이오 분자 및 세포구조 연구단
바이오 분자 및 세포구조 연구단
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Structural basis of the fanconi anemia-associated mutations within the FANCA and FANCG complex

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Title
Structural basis of the fanconi anemia-associated mutations within the FANCA and FANCG complex
Author(s)
Jeong E.; Seong-Gyu Lee; Hyun-Suk Kim; Jihyeon Yang; Shin J.; Kim Y.; Kim J.; Orlando D. Sch¨arer; Kim Y.; Jung-Eun Yeo; Homin Kim; Cho Y.
Publication Date
2020-04
Journal
NUCLEIC ACIDS RESEARCH, v.48, no.6, pp.3328 - 3342
Publisher
OXFORD UNIV PRESS
Abstract
© The Author(s) 2020. Published by Oxford University Press on behalf of Nucleic Acids Research.Monoubiquitination of the Fanconi anemia complementation group D2 (FANCD2) protein by the FA core ubiquitin ligase complex is the central event in the FA pathway. FANCA and FANCG play major roles in the nuclear localization of the FA core complex. Mutations of these two genes are the most frequently observed genetic alterations in FA patients, and most point mutations in FANCA are clustered in the C-terminal domain (CTD). To understand the basis of the FA-associated FANCA mutations, we determined the cryo-electron microscopy (EM) structures of Xenopus laevis FANCA alone at 3.35 Å and 3.46 Å resolution and two distinct FANCA-FANCG complexes at 4.59 and 4.84 Å resolution, respectively. The FANCA CTD adopts an arc-shaped solenoid structure that forms a pseudo-symmetric dimer through its outer surface. FA- and cancer-associated point mutations are widely distributed over the CTD. The two different complex structures capture independent interactions of FANCG with either FANCA C-terminal HEAT repeats, or the N-terminal region. We show that mutations that disturb either of these two interactions prevent the nuclear localization of FANCA, thereby leading to an FA pathway defect. The structure provides insights into the function of FANCA CTD, and provides a framework for understanding FA- and cancer-associated mutations
URI
https://pr.ibs.re.kr/handle/8788114/7136
ISSN
0305-1048
Appears in Collections:
Pioneer Research Center for Biomolecular and Cellular Structure(바이오분자 및 세포구조 연구단) > Journal Papers (저널논문)
Center for Genomic Integrity(유전체 항상성 연구단) > Journal Papers (저널논문)
Pioneer Research Center for Biomolecular and Cellular Structure(바이오분자 및 세포구조 연구단) > Protein Communication Group(단백질 커뮤니케이션 그룹) > Journal Papers (저널논문)
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