--- provider: perplexity model: sonar-pro cached: false start_time: '2025-11-03T22:02:20.760716' end_time: '2025-11-03T22:02:53.581271' duration_seconds: 32.82 provider_config: timeout: 600 max_retries: 3 parameters: allowed_domains: [] reasoning_effort: low search_domain_filter: [] return_citations: true temperature: 0.0 citation_count: 16 --- ## Question Research the TTC28 (Q96AY4) gene in human, focusing on its molecular function, biological processes, and cellular localization. Include information about protein domains, known interactions, and any disease associations. ## Output The **TTC28 (Q96AY4)** gene in humans encodes the **tetratricopeptide repeat domain 28** protein, which plays a critical role in mitosis, chromosomal stability, and is implicated in cancer biology. Below is a comprehensive overview based on current research and authoritative databases. --- ### 1. Key Concepts and Definitions - **Gene Name:** TTC28 (Tetratricopeptide Repeat Domain 28) - **Protein ID:** Q96AY4 - **Location:** Chromosome 22q12.1[7][9] - **Protein Length:** 2481 amino acids[5] --- ### 2. Molecular Function - **Kinase Binding:** TTC28 enables kinase binding activity, notably interacting with Aurora kinase B (AURKB), a key regulator of mitosis[1][2]. - **Chaperone-Mediated Autophagy (CMA) Substrate:** TTC28 is a substrate for HSPA8-mediated CMA/microautophagy, which regulates its degradation and links it to protein quality control and cellular homeostasis[2][4]. - **Mitotic Regulation:** TTC28 is essential for the condensation of spindle midzone microtubules and the formation of the midbody during mitosis, directly impacting cytokinesis[1][11][16]. --- ### 3. Biological Processes - **Regulation of Mitotic Cell Cycle:** TTC28 is involved in the regulation of the mitotic cell cycle, particularly in spindle midzone formation and cytokinesis[1][11][16]. - **Chromosomal Stability:** TTC28 is crucial for maintaining chromosomal stability. Its downregulation leads to increased genome instability, a hallmark of many cancers[2][4]. - **CMA and Genome Maintenance:** By interacting with HSPA8, TTC28 is involved in CMA, which is necessary for proper mitosis and genome integrity[2]. --- ### 4. Cellular Localization - **Cytoplasmic (Perinuclear):** TTC28 is predominantly localized in the cytoplasm, especially in the perinuclear region, as confirmed by confocal microscopy[2]. - **Midbody During Mitosis:** TTC28 localizes to the midbody during cell division, consistent with its role in cytokinesis[1][16]. - **Nucleolar Presence:** A minor fraction of endogenous TTC28 is detected in nucleoli[2]. --- ### 5. Protein Domains - **Tetratricopeptide Repeat (TPR) Motifs:** TTC28 contains 25 TPR motifs, which are known for mediating protein-protein interactions and are essential for its function in mitosis and interaction with HSPA8[11][2]. - **TPR Domain Function:** The TPR domains facilitate binding to the PTIEEVD motif of HSPA8, mediating its role in CMA and protein complex assembly[2]. --- ### 6. Known Interactions - **HSPA8 (Heat Shock Cognate 71 kDa Protein):** TTC28 directly interacts with HSPA8, which is central to CMA and protein degradation pathways[2][4]. - **Aurora Kinase B (AURKB):** TTC28 binds AURKB, influencing mitosis and cytokinesis[2]. - **Vimentin and DDX41:** Co-immunoprecipitation studies confirm interactions with vimentin (a cytoskeletal protein) and DDX41 (a DEAD-box helicase), suggesting roles in cytoskeletal organization and RNA processing[2]. - **Extensive Interactome:** Mass spectrometry identified 222 candidate interacting proteins, indicating TTC28’s involvement in multiple cellular pathways[2]. --- ### 7. Disease Associations - **Cancer:** TTC28 is frequently mutated and downregulated in various human cancers. Its reduced expression correlates with poor overall survival in lung cancer and is associated with increased genomic instability[2][4]. - **Cholestasis, Benign Recurrent Intrahepatic, Type 2:** TTC28 is listed as associated with this rare liver disorder, though the mechanistic link is not well characterized[1]. - **Genome Instability:** Downregulation of TTC28 contributes to chromosomal instability, a driver of tumorigenesis[2][4]. --- ### 8. Recent Developments and Latest Research (2023–2024) - **2024 Study (Zhang et al.):** Demonstrated that TTC28 is essential for CMA-mediated maintenance of chromosomal stability, directly interacts with HSPA8 and AURKB, and that its loss leads to increased genome instability in cancer cells[2][4]. - **Expression Analysis:** TTC28 mRNA and protein levels are significantly decreased in many cancers, with a strong correlation between mRNA and protein abundance across cancer cell lines and tissues[2]. --- ### 9. Expert Opinions and Analysis - **Essential for Mitosis and Cytokinesis:** Multiple studies and database entries converge on TTC28’s critical role in cell division, particularly in spindle midzone formation and midbody assembly[1][11][16]. - **Cancer Biology:** Experts highlight TTC28 as a potential tumor suppressor due to its role in maintaining genome stability and its frequent downregulation in cancer[2][4]. --- ### 10. Relevant Statistics and Data - **Interactome:** 222 candidate proteins identified as potential interactors via mass spectrometry[2]. - **Correlation Coefficient:** Spearman R = 0.78 (protein vs. mRNA in cell lines), R = 0.43 (in pancancer tissues), indicating a strong relationship between TTC28 expression at the transcript and protein levels[2]. --- ### URLs and Publication Dates - [GeneCards TTC28](https://www.genecards.org/cgi-bin/carddisp.pl?gene=TTC28) (2025) - [PMC Article: Zhang et al., 2024](https://pmc.ncbi.nlm.nih.gov/articles/PMC11648667/) (2024) - [UniProt Q96AY4](https://www.uniprot.org/uniprotkb/Q96AY4/entry) (2024) - [jPOST Database Q96AY4](https://globe.jpostdb.org/protein.php?id=Q96AY4) (2024) - [Wikipedia TTC28](https://en.wikipedia.org/wiki/TTC28) (2024) --- **Summary:** TTC28 is a large, TPR-containing protein essential for mitosis, chromosomal stability, and CMA, with a cytoplasmic and midbody localization. It interacts with key mitotic and chaperone proteins, is downregulated in many cancers, and is associated with increased genomic instability when lost or mutated[1][2][4][11][16]. ## Citations 1. https://www.genecards.org/cgi-bin/carddisp.pl?gene=TTC28 2. https://pmc.ncbi.nlm.nih.gov/articles/PMC11648667/ 3. https://marrvel.org/human/gene/23331 4. https://pubmed.ncbi.nlm.nih.gov/39630868/ 5. https://globe.jpostdb.org/protein.php?id=Q96AY4 6. https://epub.uni-regensburg.de/52688/1/Thesis%20BDLCT_final.pdf 7. https://en.wikipedia.org/wiki/TTC28 8. https://openresearch.newcastle.edu.au/ndownloader/files/54401696 9. https://varsome.com/gene/hg19/TTC28 10. https://escholarship.org/content/qt7z22d5xd/qt7z22d5xd.pdf 11. https://glygen.org/protein/Q96AY4 12. https://www.ebi.ac.uk/QuickGO/GProtein?ac=Q96AY4 13. https://glycosmos.org/glycoproteins/Q96AY4 14. https://www.promega.de/findmygene/GeneDetail.aspx?ncbiid=23331 15. https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=DetailsSearch&Term=23331 16. https://www.uniprot.org/uniprotkb/Q96AY4/entry