Model of the spectrin di-repeat as a generalized mechanosensitive protein–protein interaction motif. The N-terminal repeat is colored beige, the C-terminal repeat is light blue, and the residues critical for ankyrin binding are colored red. (Left) The βI-14,15 di-repeat is shown in a hypothetical extended conformation similar to that observed in most of the previously determined spectrin di-repeat structures. The conformation of βI-15 and the 15A-B loop are modeled in this structure using the βI-8,9 structure (PDBID: 1S35) as a reference. In this conformation, the continuity of the ankyrin-binding surface is disrupted; mutagenesis data suggest that loss of residues stabilizing the tilt angle abrogates ankyrin binding. Such a conformation might conceivably be generated by stretch across the di-repeat⁴⁴  or perhaps by other factors such as point mutations or by lipid binding.²⁰  (right) Ligand binding would alter the conformation of the linear di-repeat, inducing down-stream events (signal transduction), or the same conformational change may occur in the absence of ligand binding and under mechanical stress, inducing ligand binding. In either case, the delicate conformation of the ligand-binding pocket generated by spectrin di-repeats makes this structure an attractive candidate as a mechanosensory switch. This switch is dynamically depicted in Figure S3.