1.A.106 The Calcium Load-activated Calcium Channel (CLAC) Family Maintaining homeostasis of Ca²⁺ stores in the endoplasmic reticulum (ER) is crucial for proper Ca²⁺ signaling and key cellular functions. The Ca²⁺-release-activated Ca²⁺ (CRAC) channel is responsible for Ca²⁺ influx and refilling after store depletion. Transmembrane and coiled-coil domains protein 1 (TMCO1) is an ER transmembrane protein with 3 TMSs that actively prevents Ca²⁺ stores from overfilling, acting as a 'Cacium Load-activated Calcium channel' or 'CLAC' channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca²⁺ overloading and disassembly upon Ca²⁺ depletion and forms a Ca²⁺-selective ion channel in liposomes. TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca²⁺ in cells. Thus, TMCO1 provides a protective mechanism to prevent overfilling of ER stores with calcium ions (Wang et al. 2016). The CLAC Family was formerly the DUF106 Family.
References:
Alanay, Y., B. Ergüner, E. Utine, O. Haçariz, P.O. Kiper, E.Z. Taşkıran, F. Perçin, E. Uz, M.&.#.3.5.0.;. Sağiroğlu, B. Yuksel, K. Boduroglu, and N.A. Akarsu. (2014). TMCO1 deficiency causes autosomal recessive cerebrofaciothoracic dysplasia. Am J Med Genet A 164A: 291-304.
Batchelor-Regan, H., B. Xin, A. Zhou, and H. Wang. (2021). From Disease Description and Gene Discovery to Functional Cell Pathway: A Decade-Long Journey for TMCO1. Front Genet 12: 652400.
Li, C.F., W.R. Wu, T.C. Chan, Y.H. Wang, L.R. Chen, W.J. Wu, B.W. Yeh, S.S. Liang, and Y.L. Shiue. (2017). Transmembrane and Coiled-Coil Domain 1 Impairs the AKT Signaling Pathway in Urinary Bladder Urothelial Carcinoma: A Characterization of a Tumor Suppressor. Clin Cancer Res 23: 7650-7663.
Li, J., C. Liu, Y. Li, Q. Zheng, Y. Xu, B. Liu, W. Sun, Y. Li, S. Ji, M. Liu, J. Zhang, D. Zhao, R. Du, Z. Liu, G. Zhong, C. Sun, Y. Wang, J. Song, S. Zhang, J. Qin, S. Ling, X. Wang, and Y. Li. (2019). TMCO1-mediated Ca leak underlies osteoblast functions via CaMKII signaling. Nat Commun 10: 1589.
Sun, Z., H. Zhang, X. Wang, Q.C. Wang, C. Zhang, J.Q. Wang, Y.H. Wang, C.Q. An, K.Y. Yang, Y. Wang, F. Gao, C. Guo, and T.S. Tang. (2018). TMCO1 is essential for ovarian follicle development by regulating ER Castore of granulosa cells. Cell Death Differ. [Epub: Ahead of Print]
Wang, Q.C., Q. Zheng, H. Tan, B. Zhang, X. Li, Y. Yang, J. Yu, Y. Liu, H. Chai, X. Wang, Z. Sun, J.Q. Wang, S. Zhu, F. Wang, M. Yang, C. Guo, H. Wang, Q. Zheng, Y. Li, Q. Chen, A. Zhou, and T.S. Tang. (2016). TMCO1 Is an ER Ca²⁺ Load-Activated Ca²⁺ Channel. Cell 165: 1454-1466.
Wunderlich, J. (2022). Updated List of Transport Proteins in. Front Cell Infect Microbiol 12: 926541.
Yang, K.Y., S. Zhao, H. Feng, J. Shen, Y. Chen, S.T. Wang, S.J. Wang, Y.X. Zhang, Y. Wang, C. Guo, H. Liu, and T.S. Tang. (2022). Ca homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling. Cell Death Dis 13: 674.
Zhang, N., M. Tang, M. Wen, Y. Cao, and B. OuYang. (2020). Expression, purification and characterization of TMCO1 for structural studies. Protein Expr Purif 179: 105803. [Epub: Ahead of Print]
Zhong, W., X. Wang, L. Yang, Y. Wang, Q. Xiao, S. Yu, R.D. Cannon, Y. Bai, C. Zhang, D. Chen, P. Ji, X. Gao, and J. Song. (2022). Nanocarrier-Assisted Delivery of Metformin Boosts Remodeling of Diabetic Periodontal Tissue via Cellular Exocytosis-Mediated Regulation of Endoplasmic Reticulum Homeostasis. ACS Nano. [Epub: Ahead of Print]
Examples:
TC#	Name	Organismal Type	Example
1.A.106.1.1	The Transmembrane and coiled-coil domains protein 1 (TMCO1, TMCC4, PNAS-10, PNAS-136, UNQ155) of 188 aas and 3 TMSs. It is an ER transmembrane protein that actively prevents Ca²⁺ stores from overfilling, acting as a "Cacium Load-activated Calcium channel" or ""CLAC"" channel. TMCO1 undergoes reversible homotetramerization in response to ER Ca²⁺ overloading and disassembly upon Ca²⁺ depletion to form a Ca²⁺-selective ion channel as demonstrated in liposomes (Wang et al. 2016). TMCO1 knockout mice reproduce the main clinical features of human cerebrofaciothoracic (CFT) dysplasia spectrum, a developmental disorder linked to TMCO1 dysfunction, and exhibit severe mishandling of ER Ca²⁺ in cells (Alanay et al. 2014). Thus, TMCO1 provides a protective mechanism to prevent overfilling of ER stores with calcium ions (Wang et al. 2016). It regulates Ca²⁺ stores in granulosa cells (Sun et al. 2018). TMCO1-mediated Ca²⁺ leak underlies osteoblast functions via CaMKII signaling (Li et al. 2019). The TMCO1 gene is a tumor suppressor in urinary bladder urothelial carcinomas (UBUC). TMCO1 dysregulates cell-cycle progression via suppression of the AKT pathway, and S60 of the TMCO1 protein is crucial for its tumor-suppressor roles (Li et al. 2017). Batchelor-Regan et al. 2021 published a short review about the clinical and scientific advances made with TMCO1. Ca²⁺ homeostasis maintained by TMCO1 underlies corpus callosum development via ERK signaling (Yang et al. 2022). A mechanism of metformin action, restoring cellular ER homeostasis, enabled the development of a nanocarrier-mediated ER targeting strategy for remodeling diabetic periodontal tissue (Zhong et al. 2022).		TMCO1, a CLAC channel of Homo sapiens

1.A.106.1.10	Uncharacterized CLAC channel of 176 aas and 3 TMSs. It appears to be a calcium-selective channel required to prevent calcium stores from overfilling.		CLAC channel of Entamoeba histolytica

1.A.106.1.11	*Calcium load-activated calcium channel homolog, TMCO1, of 186 aas and 3 TMSs. The low resolution 3-dimensional structure of DdTMCO1 has been determined by solution NMR (Zhang et al.* 2020).**		*TMCO1 of Dictyostelium discoideum* (Slime mold)**

1.A.106.1.12	Calcium load-activated calcium channel, TMCO1, of 189 aas and 2 or 3 TMSs (Wunderlich 2022).		TMCO1 of Plasmodium falciparum

1.A.106.1.2	TMCO1 of 183 aas and 3 TMSs		TMCo1 of Hydra vulgaris (Hydra) (Hydra attenuata)

1.A.106.1.3	TMCO1 or Anon-37B-2(TUB2, TuB2, Tu37B2) of 177 aas (Q8IA62) or 183 aas (Q9VJ11) and 3 TMSs. It is a calcium-selective channel required to prevent calcium stores from overfilling.		*TMCO1 of Drosophila melanogaster* (Fruit fly)**

1.A.106.1.4	TMCO1 of 177 aas and 3 TMSs		*TMCO1 of Schistosoma japonicum* (Blood fluke)**

1.A.106.1.5	TMCO1 homologue of 201 aas and 3 TMSs		TMCO1 homologue of Toxoplasma gondii

1.A.106.1.6	Uncharacterized protein of 199 aas and 3 TMSs		*UP of Zea mays* (Maize)**

1.A.106.1.7	Uncharacterized protein of 219 aas and 3 TMSs		UP of Eimeria tenella (Coccidian parasite)

1.A.106.1.8	Uncharacterized protein of 196 aas and 3 TMSs		UP of Arabidopsis thaliana

1.A.106.1.9	Uncharacterized TMCO1 homologue of 192 aas and 3 TMSs.		UP of Chlamydomonas reinhardtii

Examples:
TC#	Name	Organismal Type	Example
1.A.106.2.1	TMCO1 homologue of 167 aas and 3 TMSs		TMCO1 homologue of Korarchaeum cryptofilum

1.A.106.2.2	Uncharacterized protein of 174 aas and 3 TMSs		UP of Thermococcus nautili

1.A.106.2.3	Uncharacterized protein of 191 aas and 3 TMSs.		UP of Methanobrevibacter smithii

1.A.106.2.4	Uncharacterized protein of 301 aas and 4 TMSs		UP of Halorubrum saccharovorum

1.A.106.2.5	Uncharactized protein of 193 aas and 3 or 4 TMSs		UP of Ferroglobus placidus