Fig. 8
From: Identification of rare sequence variation underlying heritable pulmonary arterial hypertension
Structural analysis of SOX17 mutations. a Schematic diagram of human SOX17 (Q9H6I2), based on UniProtKB annotation, and published reports23. Red arrows indicate PTVs and black arrows indicate missense mutations identified in PAH patients. The blue bar illustrates the region that is covered in the crystal structure (PDB: 3F27)64. The ability of SOX17 to activate transcription of target genes correlates with binding to β-catenin23. As illustrated, all PTVs lead to a loss of the β-catenin binding region. Two missense mutations are located within and very close to the minimum β-catenin binding regions, and both are highly conserved, indicating they are likely to be important for β-catenin binding. b Structural analysis of HMG domain missense mutations found in PAH patients. Left, Superposition of SOX17/DNA structure (Sox17: cyan, DNA: grey)64 onto SOX2/DNA/Oct1 structure (PDB: 1GT0, Sox2: yellow, Oct1: magenta, DNA: light blue)24. Right: Magnified view of the interactions around Arg140 in the SOX2/DNA/Oct structure. Arg140 in SOX2 makes multiple H-bond interactions and mutating this Arg in SOX2 abolishes the interaction with transcription factors Pax6 and Oct424. SOX2 and SOX17 both bind to Oct465 and SOX17 K122E mutant can replace SOX2 in maintaining stem cell pluripotency65, indicating this region in SOX17 may interact with Oct4, similar to SOX2. The three missense mutations in SOX17 will likely disrupt interaction with Oct4. c Supporting the analysis in b, sequence alignment shows that the HMG domain of SOX2 (P48431) and SOX17 as well as SOX8 (P57073) and SOX18 (P35713) share high sequence identity and the three mutations found in PAH (highlighted in yellow) are highly conserved emphasising their functional importance. Similarly, the Gly and Thr that interact with Arg140 in SOX2 (highlighted in yellow) are also conserved between Oct1 (PO2F1) and Oct4 (PO5F1)
