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, G., S. Gong, S. Lan, Y. He, Y. Sun, and Z. Zhang. (2024). TMCO1 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance. Cell Mol Biol (Noisy-le-grand) 70: 99-109.
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 regulates cell proliferation, metastasis and EMT signaling through CALR, promoting ovarian cancer progression and cisplatin resistance (Sun et al. 2024). TMCO1 is a crucial regulator of ovarian cancer progression, influencing VDAC1 through CALR and impacting diverse cellular processes (Sun et al. 2024).		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