Membrane protein topology determinants and the proposed 3-TM membrane topology for human VKOR. (A) Charged residue distribution flanking TM1 of human VKOR and Syn-VKOR. Positively charged residues are indicated by red arrowheads and negatively charged residues are indicated by filled green circles. Net charges flanking TM1 of both proteins are indicated. Boxed sequences represent the proposed TM1 according to Tie et al¹⁵  and Li et al¹⁶ . Sequence alignment was adapted from Li et al¹⁶ . (B) Distribution of charged residues flanking TM1 in the proposed 3-TM structure of human VKOR. Positively and negatively charged residues are highlighted and labeled with single letter amino acid abbreviations. (C) Distribution of the membrane interfacial anchors in the proposed 3-TM structure of human VKOR. Membrane interfacial residues and active site cysteine residues are highlighted and labeled with single letter amino acid abbreviations.