Septin

Septins are a group of GTP-binding proteins expressed in all eukaryotic cells except plants. Different septins form protein complexes with each other. These complexes can further assemble into filaments, rings and gauzes. Assembled as such, septins function in cells by localizing other proteins, either by providing a scaffold to which proteins can attach, or by forming a barrier preventing the diffusion of molecules from one compartment of the cell to another, or in the cell cortex as a barrier to the diffusion of membrane-bound proteins.
Septins have been implicated in the localization of cellular processes at the site of cell division, and at the cell membrane at sites where specialized structures like cilia or flagella are attached to the cell body. In yeast cells, they compartmentalize parts of the cell and build scaffolding to provide structural support during cell division at the septum, from which they derive their name. Research in human cells suggests that septins build cages around pathogenic bacteria, that immobilize and prevent them from invading other cells.
As filament forming proteins, septins can be considered part of the cytoskeleton. Apart from forming non-polar filaments, septins associate with cell membranes, the cell cortex, actin filaments and microtubules.

Structure

Septins are P-Loop-NTPase proteins that range in weight from 30-65 kDa. Septins are highly conserved between different eukaryotic species. They are composed of a variable-length proline rich N-terminus with a basic phosphoinositide binding motif important for membrane association, a GTP-binding domain, a highly conserved Septin Unique Element domain, and a C-terminal extension including a coiled coil domain of varying length.
Septins interact either via their respective GTP-binding domains, or via both their N- and C-termini. Different organisms express a different number of septins, and from those symmetric oligomers are formed. For example, in yeast the octameric complex formed is Cdc11-Cdc12-Cdc3-Cdc10-Cdc10-Cdc3-Cdc12-Cdc11. In humans, hexameric or octameric complexes are possible. Initially, it was indicated that the human complex was Sept7-Sept6-Sept2-Sept2-Sept6-Sept7; but recently this order has been revised to Sept2-Sept6-Sept7-Sept7-Sept6-Sept2. These complexes then associate to form non-polar filaments, filament bundles, cages or ring structures in cells.

Occurrence

Septins are found in fungi, animals, and some eukaryotic algae but are not found in plants.

	Species	Group	Septin genes
Fungi	Saccharomyces cerevisiae	Cdc3	Cdc3
Fungi	Saccharomyces cerevisiae	Cdc10	Cdc10
Fungi	Saccharomyces cerevisiae	Cdc11	Cdc11, Shs1, Spr28
Fungi	Saccharomyces cerevisiae	Cdc12	Cdc12, Spr3
Fungi	Schizosaccharomyces pombe	Spn1	Spn1
Fungi	Schizosaccharomyces pombe	Spn2	Spn2
Fungi	Schizosaccharomyces pombe	Spn3	Spn3, Spn5, Spn7
Fungi	Schizosaccharomyces pombe	Spn4	Spn4, Spn6
Fungi	Candida albicans	Cdc3	Cdc3
Fungi	Candida albicans	Cdc10	Cdc10
Fungi	Candida albicans	Cdc11	Cdc11, Sep7, Spr28
Fungi	Candida albicans	Cdc12	Cdc12, Spr3
Fungi	Aspergillus nidulans	AspD	AspD
Fungi	Aspergillus nidulans	AspB	AspB
Fungi	Aspergillus nidulans	AspA	AspA
Fungi	Aspergillus nidulans	AspC	AspC
Fungi	Aspergillus nidulans	AspE	AspE
Animals	Humans	Sept2	Sept1, Spet2, Sept4, Sept5
Animals	Humans	Sept3	Sept3, Sept9, Sept12
Animals	Humans	Sept6	Sept6, Sept8, Sept10, Sept11, Sept14
Animals	Humans	Sept7	Sept7
Animals	Caenorhabditis elegans	UNC-59	UNC-59
Animals	Caenorhabditis elegans	UNC-61	UNC-61

In yeast

There are seven different septins in Saccharomyces cerevisiae. Five of those are involved in mitosis, while two are specific to sporulation. Mitotic septins form a ring structure at the bud neck during cell division. They are involved in the selection of the bud-site, the positioning of the mitotic spindle, polarized growth, and cytokinesis. The sporulating septins localize together with Cdc3 and Cdc11 to the edges of prospore membranes.

Organization

Septins form a specialised region in the cell cortex known as the septin cortex. The septin cortex undergoes several changes throughout the cell cycle: The first visible septin structure is a distinct ring which appears ~15 min before bud emergence. After bud emergence, the ring broadens to assume the shape of an hourglass around the mother-bud neck. During cytokinesis, the septin cortex splits into a double ring which eventually disappears. How can the septin cortex undergo such dramatic changes, although some of its functions may require it to be a stable structure? FRAP analysis has revealed that the turnover of septins at the neck undergoes multiple changes during the cell cycle. The predominant, functional conformation is characterized by a low turnover rate, during which the septins are phosphorylated. Structural changes require a destabilization of the septin cortex induced by dephosphorylation prior to bud emergence, ring splitting and cell separation.
The composition of the septin cortex does not only vary throughout the cell cycle but also along the mother-bud axis. This polarity of the septin network allows concentration of some proteins primarily to the mother side of the neck, some to the center and others to the bud site.

Functions

Scaffold

The septins act as a scaffold, recruiting many proteins. These protein complexes are involved in cytokinesis, chitin deposition, cell polarity, spore formation, in the morphogenesis checkpoint, spindle alignment checkpoint and bud site selection.

Cytokinesis

Budding yeast cytokinesis is driven through two septin dependent, redundant processes: recruitment and contraction of the actomyosin ring and formation of the septum by vesicle fusion with the plasma membrane. In contrast to septin mutants, disruption of one single pathway only leads to a delay in cytokinesis, not complete failure of cell division. Hence, the septins are predicted to act at the most upstream level of cytokinesis.

Cell polarity

After the isotropic-apical switch in budding yeast, cortical components, supposedly of the exocyst and polarisome, are delocalized from the apical pole to the entire plasma membrane of the bud, but not the mother cell. The septin ring at the neck serves as a cortical barrier that prevents membrane diffusion of these factors between the two compartments. This asymmetric distribution is abolished in septin mutants.
Some conditional septin mutants do not form buds at their normal axial location. Moreover, the typical localization of some bud-site-selection factors in a double ring at the neck is lost or disturbed in these mutants. This indicates that the septins may serve as anchoring site for such factors in axially budding cells.

In filamentous fungi

Since their discovery in S. cerevisiae, septin homologues have been found in other eukaryotic species, including filamentous fungi. Septins in filamentous fungi display a variety of different shapes within single cells, where they control aspects of filamentous morphology.

''Candida albicans''

The genome of C. albicans encodes homologues to all S. cerevisiae septins. Without Cdc3 and Cdc12 genes Candida albicans cannot proliferate, other septins affect morphology and chitin deposition, but are not essential. Candida albicans can display different morphologies of vegetative growth, which determines the appearance of septin structures. Newly forming hyphae form a septin ring at the base, Double rings form at sites of hyphal septation, and a septin cap forms at hyphal tips. Elongated septin-filaments encircle the spherical chlamydospores. Double rings of septins at the septation site also bear growth polarity, with the growing tip ring disassembling, while the basal ring remaining intact.

''Aspergillus nidulans''

Five septins are found in A. nidulans. AnAspBp forms single rings at septation sites that eventually split into double rings. Additionally, AnAspBp forms a ring at sites of branch emergence which broadens into a band as the branch grows. Like in C. albicans, double rings reflect polarity of the hypha. In the case of Aspergillus nidulans polarity is conveyed by disassembly of the more basal ring, leaving the apical ring intact, potentially as a growth guidance cue.

''Ashbya gossypii''

The ascomycete A. gossypii possesses homologues to all S. cerevisiae septins, with one being duplicated. In vivo studies of AgSep7p-GFP have revealed that septins assemble into discontinuous hyphal rings close to growing tips and sites of branch formation, and into asymmetric structures at the base of branching points. Rings are made of filaments which are long and diffuse close to growing tips and short and compact further away from the tip. During septum formation, the septin ring splits into two to form a double ring. Agcdc3Δ, Agcdc10Δ and Agcdc12Δ deletion mutants display aberrant morphology and are defective for actin-ring formation, chitin-ring formation, and sporulation. Due to the lack of septa, septin deletion mutants are highly sensitive, and damage of a single hypha can result in complete lysis of a young mycelium.