DOCK11 hemizygous mutations: structural consequences and protein expression. (A) Dermatological clinical findings of patients with DOCK11 deficiency (from left to right): lobular panniculitis on feet in patient A, bullous cutaneous SLE in patient D2, and noninfectious ecthyma gangrenosum on external lateral border of the right foot in patient F. (B) Schematic overview of DOCK11 protein with the positions of patients’ DOCK11 mutations. Molecular partners described to interact with DOCK11 are mentioned below the domain they bind to. (C) 3D structure of human DOCK11, as predicted by AlphaFold2 (ribbon representation, except for DRH2, which is shown as a blue surface). Confidence is high (pLDDT > 90) for the individual domain 3D structures, whereas the 3D structure of the N- and C-terminal sequences, linkers between domains and large loops (often disordered) remain elusive (low pLDDT values indicated by asterisks). Two such very large loops are depicted with broken lines, with the amino acid intervals. Positions of the domains relative to each other also remain uncertain, except form the C2-DHR1 interface (very low PEA [predicted error alignment] values). Mutated amino acids are depicted in magenta (patients A, B, C, D, and F). D414 is predicted exposed at the surface of the C2 domain and likely to play a significant role in the C2-DRH1 interface (supplemental Figure 6A-C). L1298 is predicted with confidence as being buried with the hydrophobic core of the ARM repeats, conserved in DOCK-C proteins (Figure S6D). The region including H1336 and R1366, more variable and predicted with a lower confidence, is located at the concave surface of the ARM repeats, where interactions take place in complexes of other DOCK proteins with partners. (D) 3D structure of DHR-2 domain of human DOCK11, as predicted by AlphaFold2. The DHR-2 (in light blue) is represented to interact with CDC42 (in gray), as deduced from the superimposition of DOCK11 with the 3D structure of DOCK9 in complex with CDC42. Mutated amino acids are depicted in magenta and correspond to mutations in patients E and G. L1706 is in the hydrophobic core of DHR2 lobe A, important for dimerization. R1885 is part of DHR2 lobe B, which consists of 2 sheets predicted in direct contact with the switch 1 domain of CDC42. (E) DOCK11 expression was evaluated in activated T cells of HDs and patients (A, B, C, D1, F, and G) by western blotting. The graph shows the relative expression of DOCK11 vs HDs (set to 1) ± standard error of the mean (SEM) after normalization against Ku-70 expression.