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8.A.83 The Shisa Regulator of Short-term Neuronal Synaptic Plasticity (Shisa) Family 

The Shisa family of single-TMS proteins is characterized by an N-terminal cysteine-rich domain and a proline-rich C-terminal region. Its founding member, Xenopus Shisa, promotes head development by antagonizing Wnt and FGF signaling. A mouse brain-specific Shisa protein CKAMP44 (Shisa9) was shown to play an important role in AMPA receptor desensitization, and the same proved to be true of Shisa7 (Han et al. 2019). Sequence similarity searches against protein, genome and EST databases allowed the study of the evolutionary origin and phylogenetic distribution of Shisa homologs. In addition to nine Shisa subfamilies in vertebrates, Pei and Grishin 2012 detected distantly related Shisa homologs that possess an N-terminal domain with six conserved cysteines. These Shisa-like proteins include FAM159 and KIAA1644 mainly from vertebrates, and members from various bilaterian invertebrates and Porifera, suggesting their presence in the last common ancestor of Metazoa.

Shisa-like genes have undergone large expansions in Branchiostoma floridae and Saccoglossus kowalevskii, and appear to have been lost in certain insects. Pattern-based searches against eukaryotic proteomes also uncovered several other families of predicted single-transmembrane proteins with a similar cysteine-rich domain (Shisa/Shisa-like, WBP1/VOPP1, CX, DUF2650, TMEM92, and CYYR1).  They are collectively referred to as STMC6 proteins (single-transmembrane proteins with conserved 6 cysteines). STMC6 genes are widespread in Metazoa, with the human genome containing 17 members. Frequent occurrences of PY motifs in STMC6 proteins suggest that most of them could interact with WW-domain-containing proteins, such as the NEDD4 family E3 ubiquitin ligases, and could play critical roles in protein degradation and sorting. STMC6 proteins are likely transmembrane adaptors that regulate membrane proteins such as cell surface receptors (Pei and Grishin 2012).

Trafficking and biophysical properties of AMPA receptors (AMPARs) in the brain depend on interactions with associated proteins. Klaassen et al. 2016 identify Shisa6, a single transmembrane protein, as a stable and directly interacting bona fide AMPAR auxiliary subunit. Shisa6 is enriched at hippocampal postsynaptic membranes and co-localizes with AMPARs. The Shisa6 C-terminus harbours a PDZ domain ligand that binds to PSD-95, constraining mobility of AMPARs in the plasma membrane and confining them to postsynaptic densities. Shisa6 expressed in HEK293 cells alters GluA1- and GluA2-mediated currents by prolonging decay times and decreasing the extent of AMPAR desensitization, while slowing the rate of recovery from desensitization. Using gene deletion, it was shown that Shisa6 increases rise and decay times of hippocampal CA1 miniature excitatory postsynaptic currents (mEPSCs). Shisa6-containing AMPARs show prominent sustained currents, indicating protection from full desensitization. Accordingly, Shisa6 prevents synaptically trapped AMPARs from depression at high-frequency synaptic transmission (Klaassen et al. 2016). Shisa7 is a GABAA receptor auxiliary subunit controlling benzodiazepine actions (Han et al. 2019). Scotin (Shisa-5) can induce apoptosis in a caspase-dependent manner and plays a role in p53/TP53-dependent apoptosis. Scotin is a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane (Bourdon et al. 2002). Kim et al. 2023 proposed that SCOTIN impedes the ER-to-Golgi transport through its ability to form biomolecular condensates at the ER membrane.

References associated with 8.A.83 family:

Bourdon, J.C., J. Renzing, P.L. Robertson, K.N. Fernandes, and D.P. Lane. (2002). Scotin, a novel p53-inducible proapoptotic protein located in the ER and the nuclear membrane. J. Cell Biol. 158: 235-246. 12135983
Castellano, D., K. Wu, A. Keramidas, and W. Lu. (2022). Shisa7-dependent regulation of GABA receptor single-channel gating kinetics. J. Neurosci. [Epub: Ahead of Print] 36216503
Han, W., J. Li, K.A. Pelkey, S. Pandey, X. Chen, Y.X. Wang, K. Wu, L. Ge, T. Li, D. Castellano, C. Liu, L.G. Wu, R.S. Petralia, J.W. Lynch, C.J. McBain, and W. Lu. (2019). Shisa7 is a GABA receptor auxiliary subunit controlling benzodiazepine actions. Science 366: 246-250. 31601770
Kato, A.S. and J.M. Witkin. (2018). Auxiliary subunits of AMPA receptors: The discovery of a forebrain-selective antagonist, LY3130481/CERC-611. Biochem Pharmacol 147: 191-200. 28987594
Kim, N., T.H. Kim, C. Kim, J.E. Lee, M.G. Kang, S. Shin, M. Jung, J.S. Kim, J.Y. Mun, H.W. Rhee, S.Y. Park, Y. Shin, and J.Y. Yoo. (2023). Intrinsically disordered region-mediated condensation of IFN-inducible SCOTIN/SHISA-5 inhibits ER-to-Golgi vesicle transport. Dev Cell 58: 1950-1966.e8. 37816329
Klaassen, R.V., J. Stroeder, F. Coussen, A.S. Hafner, J.D. Petersen, C. Renancio, L.J. Schmitz, E. Normand, J.C. Lodder, D.C. Rotaru, P. Rao-Ruiz, S. Spijker, H.D. Mansvelder, D. Choquet, and A.B. Smit. (2016). Shisa6 traps AMPA receptors at postsynaptic sites and prevents their desensitization during synaptic activity. Nat Commun 7: 10682. 26931375
Nagano, T., S. Takehara, M. Takahashi, S. Aizawa, and A. Yamamoto. (2006). Shisa2 promotes the maturation of somitic precursors and transition to the segmental fate in Xenopus embryos. Development 133: 4643-4654. 17065233
Pei, J. and N.V. Grishin. (2012). Unexpected diversity in Shisa-like proteins suggests the importance of their roles as transmembrane adaptors. Cell Signal 24: 758-769. 22120523
Schmitz, L.J.M., R.V. Klaassen, M. Ruiperez-Alonso, A.E. Zamri, J. Stroeder, P. Rao-Ruiz, J.C. Lodder, R.J. van der Loo, H.D. Mansvelder, A.B. Smit, and S. Spijker. (2017). The AMPA receptor-associated protein Shisa7 regulates hippocampal synaptic function and contextual memory. Elife 6:. 29199957
Yamamoto, A., T. Nagano, S. Takehara, M. Hibi, and S. Aizawa. (2005). Shisa promotes head formation through the inhibition of receptor protein maturation for the caudalizing factors, Wnt and FGF. Cell 120: 223-235. 15680328