Cdc12

Cdc12
Name	Cdc12

Cdc12 is a formin family cytoskeletal protein essential for cytokinesis in the fission yeast Schizosaccharomyces pombe. It is a central component of the contractile ring, a structure composed of actin and myosin II filaments that assembles at the cell division plane to drive cleavage furrow ingression and cell separation. Cdc12 nucleates actin polymerization and is required for the proper assembly, stability, and constriction of the ring, making it a critical regulator of cell division fidelity.

Function and role in cytokinesis

Cdc12 is a key formin that localizes to the cell cortex at the future division site during mitosis. Its primary function is to nucleate and elongate unbranched actin filaments that form the structural backbone of the contractile ring. This activity is crucial for the initial assembly of the ring, which also incorporates myosin II motor proteins like Myo2 to generate the force needed for furrow ingression. Without functional Cdc12, cells fail to form a stable contractile ring, leading to cytokinesis failure, multinucleation, and cell death. The protein's role is tightly coordinated with other cytokinesis regulators, including the GTPase Rho1, which activates Cdc12 at the correct cellular location.

Structure and domains

The Cdc12 protein contains several conserved domains characteristic of the formin family. These include the formin homology 1 (FH1) and formin homology 2 (FH2) domains, which are essential for its function. The FH2 domain is responsible for dimerization and directly nucleates actin polymerization, while the FH1 domain, rich in proline residues, interacts with profilin-bound actin monomers to facilitate filament elongation. Cdc12 also possesses a GTPase-binding domain (GBD) that interacts with Rho1, and an adjacent Diaphanous inhibitory domain (DID), which together maintain the protein in an autoinhibited state in the cytoplasm until activated by Rho1 signaling at the cell division plane.

Regulation and phosphorylation

Cdc12 activity is tightly regulated to ensure contractile ring assembly occurs only at the proper time and place. The primary regulator is the small GTPase Rho1, which, in its active GTP-bound state, binds to the GBD of Cdc12, relieving autoinhibition and allowing its recruitment to the cell cortex. Furthermore, Cdc12 is subject to phosphorylation by several kinases. The polo kinase Plo1 phosphorylates Cdc12, which is important for its proper localization and function during mitosis. Additionally, the septation initiation network (SIN) pathway, involving kinases like Sid2 and Cdc7, regulates Cdc12 activity and contractile ring dynamics, linking its function to mitotic exit and cytokinesis progression.

Interactions with other proteins

Cdc12 forms a complex network of interactions essential for cytokinesis. Its direct binding partner Rho1 is critical for its activation and localization. Cdc12 interacts with actin-binding proteins like profilin via its FH1 domain to promote actin filament assembly. It also associates with other contractile ring components, including the myosin II heavy chain Myo2 and the IQGAP-related protein Rng2, helping to integrate actin and myosin filaments into a functional structure. Furthermore, Cdc12 interacts with proteins of the SIN pathway, such as the scaffold protein Cdc14, ensuring coordination between mitotic exit and contractile ring constriction.

Mutations and phenotypic effects

Mutations in the *cdc12* gene lead to severe cytokinesis defects. Temperature-sensitive *cdc12* mutants at the restrictive temperature fail to assemble a contractile ring, resulting in elongated, multinucleate cells that eventually lyse. Specific mutations in the FH1 or FH2 domains disrupt actin nucleation and cause ring assembly failure. Mutations affecting the regulatory GBD or DID domains can lead to constitutive activation or mislocalization of Cdc12, disrupting the spatial control of actin polymerization and causing aberrant cortical actin patches. These phenotypes highlight Cdc12's indispensable role in orchestrating the mechanical process of cell division.

Evolutionary conservation

Cdc12 is a member of the highly conserved formin family, with structural and functional homologs found throughout eukaryotes. In the budding yeast Saccharomyces cerevisiae, the homologous formins Bni1 and Bnr1 perform analogous roles in actin cable formation and cytokinesis. In metazoans, formins like Diaphanous (Dia1 in mammals) are regulated by Rho GTPases and are crucial for cytokinesis, stress fiber formation, and other actin-dependent processes. The conservation of the FH1 and FH2 domains, the autoinhibitory mechanism involving a GBD and DID, and the regulation by Rho family GTPases underscore the fundamental role of Cdc12-like formins in cytoskeletal remodeling across the tree of life.

Category:Cell biology Category:Proteins Category:Schizosaccharomyces pombe