A complete compendium of crystal structures for the human SEPT3 subgroup reveals functional plasticity at a specific septin interface

Author(s)

Silva do Vale Castro, Danielle Karoline ; de Oliveira da Silva, Sabrina Matos ; Pereira, Humberto D'Muniz ; Alves Macedo, Joci Neuby ; Leonardo, Diego Antonio ; Valadares, Napoleao Fonseca ; Kumagai, Patricia Suemy ; Brandao-Neto, Jose ; Ulian Araujo, Ana Paula ; Garratt, Richard Charles

• Document type: Journal article
• Source: IUCRJ; v. 7, p. 18-pg., 2020-05-01.

Abstract

Human septins 3, 9 and 12 are the only members of a specific subgroup of septins that display several unusual features, including the absence of a C-terminal coiled coil. This particular subgroup (the SEPT3 septins) are present in rod-like octameric protofilaments but are lacking in similar hexameric assemblies, which only contain representatives of the three remaining subgroups. Both hexamers and octamers can self-assemble into mixed filaments by end-to-end association, implying that the SEPT3 septins may facilitate polymerization but not necessarily function. These filaments frequently associate into higher order complexes which associate with biological membranes, triggering a wide range of cellular events. In the present work, a complete compendium of crystal structures for the GTP-binding domains of all of the SEPT3 subgroup members when bound to either GDP or to a GTP analogue is provided. The structures reveal a unique degree of plasticity at one of the filamentous interfaces (dubbed NC). Specifically, structures of the GDP and GTP gamma S complexes of SEPT9 reveal a squeezing mechanism at the NC interface which would expel a polybasic region from its binding site and render it free to interact with negatively charged membranes. On the other hand, a polyacidic region associated with helix alpha 5', the orientation of which is particular to this subgroup, provides a safe haven for the polybasic region when retracted within the interface. Together, these results suggest a mechanism which couples GTP binding and hydrolysis to membrane association and implies a unique role for the SEPT3 subgroup in this process. These observations can be accounted for by constellations of specific amino-acid residues that are found only in this subgroup and by the absence of the C-terminal coiled coil. Such conclusions can only be reached owing to the completeness of the structural studies presented here. (AU)

• FAPESP's process: 16/04658-9 - Structural determinants for specific interaction of interfaces G and NC of septins: validating the substitution rules in the assembly of the filament
• Grantee: Diego Antonio Leonardo Cabrejos
• Support Opportunities: Scholarships in Brazil - Doctorate
• FAPESP's process: 16/19734-2 - Molecular recognition in septins: the interface studies between SEPT7 and SEPT12
• Grantee: Danielle Karoline Silva Do Vale Castro
• Support Opportunities: Scholarships in Brazil - Master
• FAPESP's process: 14/15546-1 - Septins: comparative studies and the correlation between structure and function
• Grantee: Richard Charles Garratt
• Support Opportunities: Research Projects - Thematic Grants
• FAPESP's process: 10/20290-5 - Structural studies of human septins complex
• Grantee: Joci Neuby Alves Macedo
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• FAPESP's process: 12/00268-0 - Investigation of Aspects Important in the Structural Assembly of Human Septin Filaments
• Grantee: Sabrina Matos de Oliveira da Silva
• Support Opportunities: Scholarships in Brazil - Doctorate