Septins: Active GTPases or just GTP‐binding proteins?

Abstract

Septins are conserved cytoskeletal proteins with unique filament forming capabilities and roles in cytokinesis and cell morphogenesis. Septins undergo hetero-oligomerization and assemble into higher order structures including filaments, rings, and cages. Hetero- and homotypic interactions of septin isoforms involve alternating GTPase (G)-domain interfaces and those mediated by N- and C-terminal extensions. While most septins bind GTP, display weak GTP-hydrolysis activity and incorporate guanine nucleotides in their interaction interfaces, studies using GTPase-inactivating mutations have failed to conclusively establish a crucial role for GTPase activity in mediating septin functions. In this mini-review, we will critically assess the role of GTP-binding and -hydrolysis on septin assembly and function. The relevance of G-domain activity will also be discussed in the context of human septin mutations as well as the development of specific small-molecules targeting septin polymerization. As structural determinants of septin oligomer interfaces, G-domains are attractive targets for ligand-based inhibition of septin assembly. Whether such an intervention can predictably alter septin function is a major question for future research.

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

“…There is still much to be learnt about how the interaction between guanine nucleotides and septins is coupled to filament assembly, bundling and downstream events. Indeed, it is often difficult to separate the effects of binding from those of hydrolysis (Abbey et al, 2019). At the very least, it has been well established that nucleotide binding is necessary for the correct assembly of the G interfaces, and hydrolysis appears to research papers play an important role in this process (Zent & Wittinghofer, 2014;Weems & McMurray, 2017).…”

Reversible membrane deformations by straight DNA origami filaments

“…ATP or GTP) for multimerization. [17][18][19][20] The assembly and disassembly of such filaments is therefore highly dynamic and, in addition, tightly regulated by a multiple of stabilizing and destabilizing effector proteins and motors. [21][22][23][24][25][26] Indeed, many membrane remodelling functions, such as motility, cytokinesis and vesicle trafficking, rely on this controllable ability of the cytoskeleton to dynamically (de)polymerize at different timescales and cellular localizations.…”

Proteomic profiling of the oncogenic septin 9 reveals isoform-specific interactions in breast cancer cells

“…Septin paralogs from each of these four groups form complexes of various sizes and composition such as the palindromic hexamers and octamers of SEPT2/6/7 and SEPT2/6/7/9, respectively, which are considered as the minimal units of septin filaments (13)(14)(15). While the precise identity and diversity of septin complexes eludes our knowledge, septin-septin interactions are influenced by GTP binding and hydrolysis, the relative abundance of septin paralogs and isoforms, which can vary between cell types, and the presence of domains (e.g., N-terminal extensions) that may interfere with the Gdomain binding interface (9,(16)(17)(18)(19). Importantly, the localization and function of septin complexes appear to depend on the properties and binding partners of their individual subunits (20)(21)(22).…”