Extended Data Fig. 6: Comparing the dimerization of DNA-PKcs in the LR synaptic complex with other PIKK family dimers.

a, Structure of the two DNA-PKcs in the LR complex. The kinase domain is aligned with the homologous domains in b and c as an anchor point. b, c, Dimer of ATR–ATRIP (b) and ATM (c) showing the aligned kinase domain and corresponding N-HEAT regions in the aligned copy. The symmetric-look front views are shown at the bottom left corner. Each protomer of ATR–ATRIP and ATM is coloured the same as the corresponding DNA-PKcs protomer, in olive (the aligned copy) and dark khaki (the other copy). d, Domain organization of DNA-PKcs compared with ATR and ATM. Abbreviations are as in Fig. 1. In our model, both the ABCDE (T2609, S2612, T2620, S2624, T2638 and T2647) and the PQR (S2023, S2029, S2041, S2053 and S2056) phosphorylation sites are located within disordered loops of DNA-PKcs 2606–2720 and 1993–2084, respectively (Fig. 2b, d). The kinase active centre from the opposite side cannot reach most of the ABCDE sites unless the YRPD-interaction (YRPD-I) loop (residues 2586–2604) is peeled off from the YRPD motif (Fig. 2d). In turn, this conformational change potentially disrupts the DNA-PKcs–DNA-PKcs dimerization interface through loop 2569–2585 (Fig. 1d). Similarly, some PQR sites are located too far from the trans kinase active centre. PQR-autophosphorylation-induced changes could have a direct effect on the Ku80 CTR–DNA-PKcs interface at the bottom of the cradle (Fig. 2d), potentially inducing the domain swap of Ku80 that was previously observed³⁰.