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]

Examples:

TC#NameOrganismal TypeExample
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).

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#NameOrganismal TypeExample
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