Fig. 1: Modular organization of CRISPR–Cas systems.

In class 1 CRISPR–Cas systems, effector modules consist of multiple Cas proteins that form a crRNA-binding complex and function together in target binding and cleavage. Class 2 systems have a single multidomain crRNA-binding protein that is functionally analogous to the entire effector complex of class 1. Subtype III-E is an exception within class 1, with a single effector protein composed of several domains derived from type III-D systems. The schematic shows the typical relationships between genetic, structural and functional organization for the seven types of CRISPR–Cas systems. Protein names follow the current nomenclature. Dispensable (and/or missing in some subtypes and variants) components are indicated by dashed outlines. Cas6 is shown with a thin solid outline for type I because it is dispensable in some but essential in most systems and with a dashed line for type III because most of these apparently use the Cas6 protein provided in trans by other CRISPR–cas loci. New type VII has a unique effector protein (Cas14) composed of two domains: β-CASP family RNase fused to a domain homologous to the C terminal of Cas10. The three colours for Cas9, Cas10, Cas12 and Cas13 each reflect the fact that these proteins contribute to different stages of the CRISPR–Cas activity. The CARF and HEPN domains often fused in a single protein are the most common sensors and effectors, respectively, in the type III ancillary modules but several alternative sensors and effectors have been identified as well and are discussed in more detail in the main text. RING nucleases (Crn) cleave cyclic oligoA produced by Cas10 and thus control the indiscriminate RNase activity of the HEPN domain of a CARF protein³⁰. HRAMP and ARAMP are array-less CRISPR-like systems derived from type III, which are typically associated with different nucleases, most often of HNH and PD-(D/E)xK families. ^*Putative small subunit that is fused to the large subunit in several type I subtypes. ^**This function can be performed by unrelated proteins; HD, HNH and PD-(D/E)K, nucleases of the respective superfamilies; LS, large subunit; RT, reverse transcriptase.