Septins are membrane-associated, GTP-binding proteins that are present in most eukaryotes. They polymerize to play important roles as scaffolds and/or diffusion barriers as part of the cytoskeleton. α-Helical coiled-coil domains are believed to contribute to septin assembly, and those observed in both human SEPT6 and SEPT8 form antiparallel homodimers. These are not compatible with their parallel heterodimeric organization expected from the current model for protofilament assembly, but they could explain the interfilament cross-bridges observed by microscopy. Here, the first structure of a heterodimeric septin coiled coil is presented, that between SEPT14 and SEPT7; the former is a SEPT6/SEPT8 homolog. This new structure is parallel, with two long helices that are axially shifted by a full helical turn with reference to their sequence alignment. The structure also has unusual knobs-into-holes packing of side chains. Both standard seven-residue (heptad) and the less common 11-residue (hendecad) repeats are present, creating two distinct regions with opposite supercoiling, which gives rise to an overall straight coiled coil. Part of the hendecad region is required for heterodimerization and therefore may be crucial for selective septin recognition. These unconventional sequences and structural features produce a metastable heterocomplex that nonetheless has enough specificity to promote correct protofilament assembly. For instance, the lack of supercoiling may facilitate unzipping and transitioning to the antiparallel homodimeric state.

Link https://www.modelarchive.org/doi/10.5452/ma-ehtvp
AF-multimer modelling, full-length 6-7 septins. Password: DfF6ySmh4d

Link https://www.modelarchive.org/doi/10.5452/ma-hv5qb
AF-multimer modelling, full-length 8-7 septins. Password: gLnx320ZKb

Link https://www.modelarchive.org/doi/10.5452/ma-i51oe
AF-multimer modelling, full-length 10-7 septins. Password: 4kH2R5iuYl

Link https://www.modelarchive.org/doi/10.5452/ma-rsp0h
AF-multimer modelling, full-length 11-7 septins. Password: kyLAresC9I

Link https://www.modelarchive.org/doi/10.5452/ma-orsg7
AF-multimer modelling, full-length 14-7 septins. Password: YkqZVAtwZo

Link https://www.modelarchive.org/doi/10.5452/ma-7fisk
AF-multimer modelling, CTD 6-7 septins. Password: tQsHMe0mpk

Link https://www.modelarchive.org/doi/10.5452/ma-qnkm5
AF-multimer modelling, CTD 8-7 septins. Password: hL53s0vHvN

Link https://www.modelarchive.org/doi/10.5452/ma-q0d1q
AF-multimer modelling, CTD 10-7 septins. Password: U02KEuEdql

Link https://www.modelarchive.org/doi/10.5452/ma-5x7mb
AF-multimer modelling, CTD 11-7 septins. Password: 2yhGa3bn9u

Link https://www.modelarchive.org/doi/10.5452/ma-zpgr8
AF-multimer modelling, CTD 14-7 septins. Password: YYGGeRMwgO

Portable Document Format (PDF) file https://doi.org/10.1107/S2059798323006514/jb5058sup1.pdf
Supplementary Tables and Figures.

PDB reference: metastable SEPT14–SEPT7 heterodimeric coiled coil, 8sjj

SASBDB references: MBP-SEPT6c + SUMO-SEPT7c, SASDR39; MBP-SEPT8c + SUMO-SEPT7c, SASDR49; MBP-SEPT10c + SUMO-SEPT7c, SASDR59; MBP-SEPT11c + SUMO-SEPT7c, SASDR69; MBP-SEPT14c + SUMO-SEPT7c, SASDR79