Fig. 7

Disorder-to-order transitions predicted by AlphaFold3 may aid structure-based variant interpretation. a) The secondary structure annotation according to STRIDE for the AlphaFold3 3D model of the heat-shock beta-1 protein (HSPB1, Uniprot ID: P04792) in its monomeric (top), dimeric (middle) and tetrameric form (bottom). The disorder-to-order transition of the N-terminus is supported by the decrease of predicted coil elements in the dimeric and tetrameric organization of the protein with respect to its monomeric form and the corresponding increase of alpha-helices. In panels b), c) and d) the AlphaFold3 models of P04792 monomer, dimer and tetramer are shown respectively. Colors correspond to the legend in a) and only one chain is highlighted for the dimer and tetramer. The C-terminus is not displayed in its entirety as indicated by the dashed black lines of panel b) and c). The position with the variant P39L is highlighted in black. The disorder-to-order transition as predicted by STRIDE corresponds to the new alpha-helices of the dimer and tetramer visible in panel c) and d). e) Motif prediction of HSPB1 (P04792) using SHARK-capture. Conserved motifs of the disordered regions are colored by their SHARK-capture score, benign and pathogenic variants are marked. Pathogenic mutations fall into SHARK-capture motifs in the N- and C-terminal regions while benign mutations do not. The P39L pathogenic variant is located within a conserved PEEWS motif