Figure 3: Structure and aggregation propensity of human WT α-Gal.

(a) Human α-Gal is a homodimer (PDB 3GXP)⁵⁴ in which each monomer contains a (β/α)8 domain (central part, yellow and green), where the active site is located and an antiparallel β-domain (central part, orange and blue). The structure was visualized with YASARA (ref. 53). (b) The intrinsic aggregation propensity of the α-Gal sequence as predicted by the TANGO algorithm reveals three strongly aggregation-prone regions: (1) M₂₈₄ALWAIMA₂₉₁; (2) L₃₄₇AWAVAMI₃₅₅; and (3) Y₃₆₅TIAVAS₃₇₁. The regions predicted by TANGO were indicated in the structure with numbers 1, 2 and 3 and were coloured in red (Fig. 1a). (c) Scatter plots representing the results of computational gatekeeper scans for each of the aggregation prone regions of α-Gal (ΔΔG FoldX versus ΔTANGO). For the TANGO region 2 mutation A348R could be identified (green amino acid residue in Fig. 1a), whereas for the TANGO region 3 mutations A368R and A368P (green amino acid residue in Fig. 1a) were identified.