Fig. 6 | Nature Communications

Fig. 6

From: Identification of rare sequence variation underlying heritable pulmonary arterial hypertension

Fig. 6

Structural analysis of ATP13A3 mutations. a Topology of ATP13A3, plotted according to UniProtKB Q9H7F0. Frameshift and stop-gained mutations identified in PAH cases are shown as khaki circles, and missense mutations as red circles. Frameshift/stop-gained mutations are predicted to truncate the protein prior to the catalytic domain and essential Mg binding sites, leading to loss of ATPase activity. b Sequence alignment of ATP13A3 with ATP1A1 (P05024), of which the high resolution structure was used for the structural analysis in c. The conserved regions of ATP13A3 and ATP1A1, essential for ATPase activity62, show good alignment (data not shown). Only regions containing the missense PAH mutations are shown, with positions of the four missense mutations highlighted in yellow above the sequences. c Structural analysis of the 4 PAH missense mutations plotted on the ATP1A1 crystal structure based on the sequence alignment in b (PDB: 3wgu)63. Green: α subunit (P05024), cyan: β subunit (P05027), grey: γ-subunit transcript variant a (Q58k79). Y535, Y677, R685 and I787 are the numbering in ATP1A1. Positions of the four missense mutations found in PAH are labelled and highlighted by red circles. d Magnified view of the cytoplasmic region of the ATPase, showing the presence of ADP at the active site. The conserved regions essential for ATPase activity are shown in light pink. The L675V and R858H mutations are located close to the ATP catalytic region

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