Panel A shows a topological arrangement of four numbered helices with gray and green structural regions; Panel B shows a protein structural model with an enlarged view highlighting four helices and the P245 residue; Panel C shows an hOrai1 homology model based on 4HKR, highlighting the P245 residue; Panel D shows the dOrai P288L 6AKI structure, highlighting the corresponding P245L (P288L) mutation.
Potential structural rearrangement of the TM4 due to the P245L mutation in Orai1. (A) Top view of the Orai1 outer interface between the TM4 and TM2/TM3 unit (green). (B) Side view of the outer interface (green), as well as a zoom-in on the disease-relevant residue P245 (red). Circles with numbers indicate the TMs, e.g., 1 corresponding to TM1. (C) Schematic depiction of the Orai1 homology model based on PDB accession no. 4HKR. The proline at position 245, marked in red, introduces a kink between the two helices colored in yellow that adds to the stabilization of the resting state. (D) This scheme of the resolved dOrai1 P288L (PDB accession no. 6AKI) structure corresponds to the human Orai1 mutation P245L. The mutation leads to an extension of TM4, shown in yellow. While this prominent extension was observed in the resolved structure, additional cryo-EM suggests a less pronounced effect, depicted by the lighter yellow helices.