Journal
CELL
Volume 165, Issue 4, Pages 949-962Publisher
CELL PRESS
DOI: 10.1016/j.cell.2016.04.003
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Funding
- JST
- PRESTO
- JSPS KAKENHI [26291010, 15H01463]
- Platform for Drug Discovery, Informatics, and Structural Life Science from the Ministry of Education, Culture, Sports, Science and Technology
- US Department of Health and Human Services
- NIH through the NIMH [5DP1-MH100706, 1R01-MH110049]
- Waterman Award from the National Science Foundation
- New York Stem Cell Foundation
- Simons Foundation
- Paul G. Allen Family Foundation
- Vallee Foundation
- Basic Science and Platform Technology Program for Innovative Biological Medicine from the Japan Agency for Medical Research and Development, AMED
- Council for Science
- Grants-in-Aid for Scientific Research [16J08032, 15H01463, 26291010] Funding Source: KAKEN
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Cpf1 is an RNA-guided endonuclease of a type V CRISPR-Cas system that has been recently harnessed for genome editing. Here, we report the crystal structure of Acidaminococcus sp. Cpf1 (AsCpf1) in complex with the guide RNA and its target DNA at 2.8 angstrom resolution. AsCpf1 adopts a bilobed architecture, with the RNA-DNA heteroduplex bound inside the central channel. The structural comparison of AsCpf1 with Cas9, a type II CRISPR-Cas nuclease, reveals both striking similarity and major differences, thereby explaining their distinct functionalities. AsCpf1 contains the RuvC domain and a putative novel nuclease domain, which are responsible for cleaving the non-target and target strands, respectively, and for jointly generating staggered DNA double-strand breaks. AsCpf1 recognizes the 50-TTTN-30 protospacer adjacent motif by base and shape readout mechanisms. Our findings provide mechanistic insights into RNA-guided DNA cleavage by Cpf1 and establish a framework for rational engineering of the CRISPR-Cpf1 toolbox.
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