Fig. 5

Structural modeling of KLHL7 demonstrates the domain-dependent correlation between genotype and phenotype. a A model of the domain topology of KLHL7 and coding variants are illustrated. The BTB domain is shown in the yellow box, the 3-box motif is shown in the blue box, the BACK domain is shown in the dark mustard box, and the Kelch domain is shown in the green box. Each RP variant is shown in magenta, and each BOS-3 variant is shown in pink. b Three-dimensional structure of the KLHL7 homodimer in complex with Cullin is shown based on the previously proposed model. Cullin is shown in orange, and each domain of KLHL7 is color-coded corresponding to panel A. The locations of each coding variant are shown in the circles. c Structural modeling of the KLHL7 BTB-BACK domain is shown in complex with Cullin. The bottom left panel shows a magnified view of wild-type (WT) KLHL7 3-box motif (cyan) interacting with the N-terminus of Cullin (orange). The bottom right panel shows a magnified view of mutations at the 3-box motif of KLHL7. Each mutation is shown in magenta. c.433A > T:p.(Asn145Tyr) disrupts the direct interaction of the motif with the N-terminus of Cullin, while c.458C > T:p.(Ala153Val) and c.472 T > C:p.(Cys158Arg) disrupt the unique structural conformation of the 3-box motif. d Structural modeling of mutations found at the Kelch domain of KLHL7 is illustrated. The Kelch domain is formed by six-β-blades forming a β-propeller structure. Each blade is numbered from the N-terminus. The dotted box shows the ligand recognition loops of the Kelch domain. Mutations are shown in magenta and the glutamates that make charge-charge interaction with the mutated arginines are shown in blue. These charge-charge interactions are lost upon mutation