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| Securin | |
|---|---|
| Name | Securin |
| Uniprot | P46108 |
| Organism | Homo sapiens |
| Length | 202 aa |
| Localization | Nucleus, cytoplasm |
Securin is a regulatory protein that controls sister chromatid separation during mitosis and meiosis through inhibition of the protease separase. Discovered through studies of chromosomal instability and oncogenesis, it is encoded in humans by the PTTG1 gene and has been analyzed in model organisms including Saccharomyces cerevisiae, Drosophila melanogaster, and Mus musculus. Securin integrates signals from the anaphase-promoting complex and the spindle assembly checkpoint to coordinate chromosome segregation and has been implicated in tumorigenesis and developmental processes.
Securin is a small, intrinsically disordered protein of approximately 200 amino acids in mammals, lacking a stable globular fold and characterized by low-complexity regions and short linear motifs. Structural studies combine sequence analysis with limited crystallographic and cryo-EM data for securin–separase complexes derived from Saccharomyces and Schizosaccharomyces pombe homologs, revealing an extended conformation that docks onto separase and masks its catalytic site. Conserved motifs include a D-box (destruction box) recognized by the anaphase-promoting complex and a separase-binding motif; phosphorylation sites cluster in regions targeted by kinases such as Cyclin-dependent kinase 1 and Aurora B kinase. Post-translational modifications and interaction interfaces mediate binding to adaptor proteins including CDC20 and CDH1 that specify ubiquitin ligase targeting.
Securin functions as a key inhibitor of chromatid separation by binding and inhibiting separase until the metaphase-to-anaphase transition. Through its interaction with the spindle assembly checkpoint components such as MAD2 and BUBR1, securin helps enforce metaphase arrest in response to unattached kinetochores, coordinating with Cyclin B1 and the Cdc20–APC/C axis. Beyond separase inhibition, securin influences centrosome stability, DNA repair pathways, and transcriptional programs via interactions with factors like p53, E2F1, and Ku70/80, linking chromosome segregation to checkpoint signaling and genomic integrity maintenance.
Securin binds directly to separase, occluding the active site and preventing proteolytic cleavage of cohesin subunits such as Rad21 (also known as SCC1) and Rec8 during meiosis. At the onset of anaphase, activation of the anaphase-promoting complex (APC/C) with co-activator CDC20 leads to ubiquitination of securin via its D-box and subsequent proteasomal degradation, liberating separase to cleave cohesin and permit sister chromatid disjunction. Parallel regulation involves securin phosphorylation that can modulate APC/C recognition, and in some organisms direct separase autoinhibition and securin-independent pathways provide redundancy with regulators such as Scc1 proteolytic control and shugoshin-mediated protection of centromeric cohesion.
Securin is regulated by ubiquitin-mediated proteolysis, phosphorylation, and protein–protein interactions. Cyclin-dependent kinases including CDK1 phosphorylate securin at conserved serine/threonine residues, influencing binding to separase and recognition by APC/C–CDC20. Aurora kinases and Plk1 phosphorylate additional sites that affect stability and subcellular localization. Ubiquitin ligases such as APC/C and deubiquitinases counterbalance turnover; proteins like USP9X and BRCA1 have been linked to modulation of securin ubiquitination in context-specific studies. Sumoylation and acetylation have been reported in specific models, modifying interaction affinities with factors such as p300 and chromatin-associated proteins.
During embryogenesis and germ cell development, securin contributes to proper chromosome segregation in mitotic and meiotic divisions. In oogenesis and spermatogenesis studied in Mus musculus and Xenopus laevis, securin controls the timing of separase activation for meiotic divisions, where protection of sister chromatid cohesion by proteins like shugoshin interacts functionally with securin pathways. Genetic knockout and knockdown experiments in Drosophila melanogaster and mouse models reveal roles in early embryonic cell cycles, organogenesis, and maintenance of stem cell populations, with loss or overexpression producing aneuploidy, developmental arrest, or altered proliferation.
Aberrant expression or mutation of securin/ PTTG1 is associated with chromosomal instability and has been observed in multiple human cancers including breast cancer, pituitary adenomas, thyroid carcinoma, colorectal cancer, and lung cancer. Overexpression can promote oncogenic transformation via induction of aneuploidy, upregulation of growth factors such as FGF2, and interference with tumor suppressors like p53 and RB1. Conversely, securin deficiency may cause genome instability and sensitivity to DNA damage. Securin has been explored as a prognostic biomarker and therapeutic target; studies have investigated small-molecule modulators, siRNA approaches, and interactions with chemotherapeutics used in clinical trials.
Securin homologs are conserved across eukaryotes, with functional counterparts including yeast Pds1 in Saccharomyces cerevisiae, Cut2 in Schizosaccharomyces pombe, and vertebrate PTTG1 paralogs. Sequence conservation is limited to short linear motifs such as the APC/C recognition D-box and separase-binding elements, while overall intrinsic disorder permits evolutionary divergence. Comparative genomics across taxa including Arabidopsis thaliana, Caenorhabditis elegans, and protozoa reveal conserved roles in chromosome segregation, though some lineages employ securin-independent separase regulation. Phylogenetic studies link securin evolution to emergence of complex mitotic controls in opisthokonts and metazoans.
Category:Cell cycle proteins