Caskin1, also known as Calcium/calmodulin-dependent serine protein kinase (CASK)-interacting protein 1, is a key multi-domain neuronal scaffold protein. It directly binds to the synaptic adaptor protein CASK, and is involved in organizing the active zones of neural synapses, potentially playing a role in neural function regulation through protein-protein interactions and lipid-binding [2,3,4,5,6].

Caskin1-knockout (Caskin1-KO) mice studies have revealed its diverse functions. These mutant mice showed differences in gait, enhanced nociception, anxiety-like behavior, stronger freezing responses in fear conditioning tests, and low memory retention in the Barnes Maze test. This indicates that Caskin1 contributes to a wide range of behavioral phenotypes in the central nervous system [2]. In addition, a missense variant D1204N in Caskin1's proline-rich region was found to segregate with psychosis in a three-generation family, suggesting Caskin1 as a high-penetrance gene candidate for psychosis development [1].

In conclusion, Caskin1 is crucial for multiple biological processes in the nervous system, including gait, nociception, memory, and stress response. The Caskin1-KO mouse models have provided valuable insights into its role in these processes and its potential association with psychosis, highlighting its importance in understanding neural function and related disease mechanisms.

References:

1. Wahbeh, Marah H, Peng, Xi, Bacharaki, Sofia, Stefanis, Nikos C, Avramopoulos, Dimitrios. 2023. A Missense Variant in CASKIN1's Proline-Rich Region Segregates with Psychosis in a Three-Generation Family. In Genes, 14, . doi:10.3390/genes14010177. https://pubmed.ncbi.nlm.nih.gov/36672919/

2. Katano, Tayo, Takao, Keizo, Abe, Manabu, Sakimura, Kenji, Ito, Seiji. 2018. Distribution of Caskin1 protein and phenotypic characterization of its knockout mice using a comprehensive behavioral test battery. In Molecular brain, 11, 63. doi:10.1186/s13041-018-0407-2. https://pubmed.ncbi.nlm.nih.gov/30359304/

3. Stafford, Ryan L, Hinde, Elizabeth, Knight, Mary Jane, Gratton, Enrico, Bowie, James U. . Tandem SAM domain structure of human Caskin1: a presynaptic, self-assembling scaffold for CASK. In Structure (London, England : 1993), 19, 1826-36. doi:10.1016/j.str.2011.09.018. https://pubmed.ncbi.nlm.nih.gov/22153505/

4. Tőke, Orsolya, Koprivanacz, Kitti, Radnai, László, Liliom, Károly, Buday, László. 2021. Solution NMR Structure of the SH3 Domain of Human Caskin1 Validates the Lack of a Typical Peptide Binding Groove and Supports a Role in Lipid Mediator Binding. In Cells, 10, . doi:10.3390/cells10010173. https://pubmed.ncbi.nlm.nih.gov/33467043/

5. Stafford, Ryan L, Ear, Jason, Knight, Mary Jane, Bowie, James U. 2011. The molecular basis of the Caskin1 and Mint1 interaction with CASK. In Journal of molecular biology, 412, 3-13. doi:10.1016/j.jmb.2011.07.005. https://pubmed.ncbi.nlm.nih.gov/21763699/

6. Koprivanacz, Kitti, Tőke, Orsolya, Besztercei, Balázs, Buday, László, Liliom, Károly. 2017. The SH3 domain of Caskin1 binds to lysophosphatidic acid suggesting a direct role for the lipid in intracellular signaling. In Cellular signalling, 32, 66-75. doi:10.1016/j.cellsig.2017.01.019. https://pubmed.ncbi.nlm.nih.gov/28104445/