Figure 6. Analysis of the novel p.L14H BAP1 variant.
(A) Schematic of BAP1 protein showing the position of the novel p.L14H missense variant (gray triangle) in comparison to known BAP1 missense mutations associated with sporadic RCC (black triangles). Data compiled from Peña-Llopis et al., Hakimi et al., COSMIC and KIRC (TCGA) (11, 21, 24). UCH, ubiquitin C-terminal hydrolase domain (blue); HBM, HCF-1-binding motif (yellow); ULD, Uch37-like domain (black); BRCA1, putative BRCA1-interacting domain (red); NLS, nuclear localization signal (green). (B) BAP1 amino acid conservation across species assessed with BioEdit’s ClustalW multiple alignment function. Protein sequences are from UniProt (Q92560, H9G0D9, F6TYN2, E2R9Z2, D3ZH56, Q99PU7, G1PS27, F6SMM8, F6RI15, Q5F3N6, Q52L14, H2UEV1, A1L2G3, Q7K5N4, Q17N72) and Ensembl (ENSPTRP00000025898) (33). (C) In silico predicted effects of the novel p.L14H missense variant and the surrounding sporadic RCC-associated missense mutations assessed with PROVEAN, SIFT and PolyPhen-2 prediction tools (19, 25, 26). (D) BAP1 structure model. Left Panel: Cartoon depiction of the BAP1 UCH domain (purple) noting p.Leu14 (red sphere) involved in organizing a flexible crossover loop and other flexible portions of the domain (salmon) that order upon ubiquitin substrate (cyan) binding. Uch37-like domain (ULD) is shown in green. Right Upper Panel: Zoom-in of wild type BAP1 leucine 14 residue with atom radii depicted in dots interacting with surrounding residues (side chains within 4 Å displayed in stick). Right Lower Panel: Zoom-in of BAP1 histidine 14 mutant with atom radii (dots) revealing clashes with surrounding residues.