期刊
NATURE STRUCTURAL & MOLECULAR BIOLOGY
卷 29, 期 8, 页码 813-+出版社
NATURE PORTFOLIO
DOI: 10.1038/s41594-022-00766-y
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资金
- David Rockefeller Graduate Program
- National Science Foundation Graduate Research Fellowship [1946429]
- NIH cancer biology training grant [T32 CA009673]
- NIH [5 R35 CA210036]
- Breast Cancer Research Foundation [BCRF-19-036]
- Howard Hughes Medical Institute, NIH [5 R01 GM126891]
- Blavatnik Family Foundation
- Damon Runyon Cancer Research foundation [DRG 2337-19]
- Division Of Graduate Education
- Direct For Education and Human Resources [1946429] Funding Source: National Science Foundation
This study reports a cryo-EM structure of human CST-Pol alpha/primase and reveals an evolutionarily conserved interaction between POLA1 and CTC1. The binding mode of CST to the N-terminus of POLA1 is revealed by negative-stain EM and cross-linking mass spectrometry. In addition, disease mutations associated with Coats plus syndrome disrupt protein-protein interfaces observed in the recruitment state.
The CST-Pol alpha/primase complex is essential for telomere maintenance and functions to counteract resection at double-strand breaks. We report a 4.6-angstrom resolution cryo-EM structure of human CST-Pol alpha/primase, captured prior to catalysis in a recruitment state stabilized by chemical cross-linking. Our structure reveals an evolutionarily conserved interaction between the C-terminal domain of the catalytic POLA1 subunit and an N-terminal expansion in metazoan CTC1. Cross-linking mass spectrometry and negative-stain EM analysis provide insight into CST binding by the flexible POLA1 N-terminus. Finally, Coats plus syndrome disease mutations previously characterized to disrupt formation of the CST-Pol alpha/primase complex map to protein-protein interfaces observed in the recruitment state. Together, our results shed light on the architecture and stoichiometry of the metazoan fill-in machinery.
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