Fig 1: Architecture of the CWC15, CTNNBL1 and CDC5L sub-complex in relation to the core Prp19 complex. (A) Architecture of the mammalian Prp19 complex. Based on biochemical and structural information, including negative staining electron microscopy of purified proteins, the core Prp19 complex is thought to consist of an extended structure formed by a tetramer of PRPF19 with the coiled-coil regions in its centre and the WD40 domains on the outside. A single copy of CDC5L is associated with the coiled-coil region of the PRPF19 tetramer through its less conserved carboxy-terminal region, designated as the spliceosomal interacting domain, whereas the more conserved N-terminal portion containing the MYB domains and NLS region is thought to associate with CTNNBL1. One copy of SPF27 is also found in association with the central portion of the PRPF19 tetramer which also contains the N-terminal region of PLRG1. CWC15 and CTNNBL1 have been described as a separate stable complex outside the Prp19 core, but are also found in association with the Prp19 complex through interaction with the N-terminal region of CDC5L. The precise configuration of the CTNNBL1/CWC15/CDC5L sub-complex (dotted ellipse) within the core Prp19 complex had not been fully defined but was expected to adopt a linear conformation. The positioning of HSP7C, a sub stoichiometric component has not been characterized (Model based on Grote et al. (30)). (B) Changes in the interactions between CWC15, CTNNBL1 and CDC5L in relation to the different spliceosomal complexes. CTNNBL1 and CWC15 form a stable dimer with the N-terminal of CTNNBL1 bound to the C-terminus of CWC15 (orange). In the B and Bact forms of the spliceosome, the Prp19 complex is stabilized by the presence of CTNNBL1, enhancing the otherwise weak interactions between CWC15 and CDC5L. CTNNBL1 acts as bridge, binding the N-terminal NLS region of CDC5L (green squiggle) through its CTD region and the C-terminus of CWC15 through its N-terminal HEAT-like region. This allows for a three-way interaction facilitating binding between the MYB domain of CDC5L (green triangular forms) and a region in the central portion of CWC15 (red squiggle). This stable three-way interaction maintains the normal levels of the Prp19 complex in B and Bact spliceosomes. At the later C stage of the spliceosome complex, CTNNBL1 is not present, and the NLS region of CDC5L can interact with the C terminal region of CWC15.