Hypothetical mechanism explaining how actin filament length changes can lead to rearrangements of the spectrin-actin lattice in the absence of Tmod1. (Top left) Model depicting the short actin filaments in expanded views of the spectrin-actin lattice of wild-type RBCs. The actin filaments are all the same length (16 subunits long), capped by Tmod1 at their pointed ends, α/β-adducin at their barbed ends, and with 2 TMs (TM5NM1 and TM5b) bound along their sides. On average, 6 spectrin-4.1R complexes are attached to each filament, creating the hexagonal lattice structure. (For simplicity, dematin is not included). (Top right) Hypothetical model depicting actin filament length redistributions in the absence of Tmod1. Substitution of Tmod3 for Tmod1 results in some filaments with normal lengths as in wild type, but insufficient levels of Tmod3 result in some uncapped filaments that either depolymerize or elongate, resulting in shorter or longer actin filaments. These shorter or longer filaments might have variable numbers of spectrin-4.1R attachments, resulting in irregular network organization and a more open lattice with larger pore sizes (Figure 4A-B). RBC TMs span along 6 actin filament subunits, requiring that actin filaments must be at least 12 subunits long for TM binding. Thus, TMs will dissociate from depolymerizing RBC filaments and associate with elongating filaments. TMs can be stabilized on longer actin filaments by virtue of TM head-to-tail self-association²⁰  and TM-actin capping by Tmod3,¹²  accounting for no net changes in TMs in the absence of Tmod1.