2.A.92 The Choline Transporter-like (CTL) Family The CTL family (solute carrier family 44; XYPPX repeat family) includes several characterized choline transporters including CTL-1 and CTL-2. Many sequence divergent family members including several paralogues in a single organism. Some of them include a hydrophobic C-terminal Duf580 domains (residues 260-625 in CTL-1). These proteins may have 9-13 TMSs. A hydrophilic domain between putative TMSs 1 and 2 is present in CTL-1 and CTL-2. The human CTL-1 is called the CDW92 antigen. This protein, also called SLC44A1, is present in both the plasma and mitochondrial membranes where it is able to transport choline at high affinity and in a Na⁺-independent manner.The properties and involvement in human diseases has been reviewed (Traiffort et al. 2013). One member of the family, TC# 2.A.92.1.7; SLC44A4, is a highly glycolsylated thiamine pyrophosphate uptake porter (Nabokina et al. 2016). Members of this family have been proposed to have the SLC44 fold (Ferrada and Superti-Furga 2022). The topologies of skeletal muscle-specific choline transporter-like protein 1 (mCTL1) has been identified, and mCTL1 mRNA and protein expression have been characterized (Yuan et al., 2004). mCTL1 is a 653-amino-accid protein with 8-11 putative transmembrane domains, three N-glycosylations sites and seven protein kinase C phosphorylation sites. The mCTL1 gene is localized to chromosome 4B2, at 182 kb in length, and encoded by 17 exons. Although the mCTL1 mRNA was expressed in several mouse tissues such as muscle, brain, heart and testis, the protein analyses of multiple tissues and membrane vesicles revealed that mCTL1 is exclusively expressed in skeletal muscle. Expression of His-tagged mCTL1 in Cos-7 cells produced an increase in saturable choline uptake that was sensitive to a Na⁺-ion gradient, ethanolamine and the Ca²⁺-channel blocker verapamil. Members of this family are difficult to predict topologically and they show weak sequence similarity with proteins of different topologies including subunits of NADH dehydrogenase. Repeat units of various lengths can be found in some of these homologues.
References:
Bryk, A.H. and J.R. Wiśniewski. (2017). Quantitative Analysis of Human Red Blood Cell Proteome. J Proteome Res 16: 2752-2761.
Dettmer, J., R. Ursache, A. Campilho, S. Miyashima, I. Belevich, S. O'Regan, D.L. Mullendore, S.R. Yadav, C. Lanz, L. Beverina, A. Papagni, K. Schneeberger, D. Weigel, Y.D. Stierhof, T. Moritz, M. Knoblauch, E. Jokitalo, and Y. Helariutta. (2014). CHOLINE TRANSPORTER-LIKE1 is required for sieve plate development to mediate long-distance cell-to-cell communication. Nat Commun 5: 4276.
Ferrada, E. and G. Superti-Furga. (2022). A structure and evolutionary-based classification of solute carriers. iScience 25: 105096.
Gao, Y.Q., J.G. Chen, Z.R. Chen, D. An, Q.Y. Lv, M.L. Han, Y.L. Wang, D.E. Salt, and D.Y. Chao. (2017). A new vesicle trafficking regulator CTL1 plays a crucial role in ion homeostasis. PLoS Biol 15: e2002978.
Iwao, B., M. Yara, N. Hara, Y. Kawai, T. Yamanaka, H. Nishihara, T. Inoue, and M. Inazu. (2016). Functional expression of choline transporter like-protein 1 (CTL1) and CTL2 in human brain microvascular endothelial cells. Neurochem Int 93: 40-50.
Kleopa, K.A. (2011). Autoimmune channelopathies of the nervous system. Curr Neuropharmacol 9: 458-467.
Kommareddi, P.K., T.S. Nair, Y. Raphael, S.A. Telian, A.H. Kim, H.A. Arts, H.K. El-Kashlan, and T.E. Carey. (2007). Cochlin isoforms and their interaction with CTL2 (SLC44A2) in the inner ear. J Assoc Res Otolaryngol 8: 435-446.
Kraner, M.E., K. Link, M. Melzer, A.B. Ekici, S. Uebe, P. Tarazona, I. Feussner, J. Hofmann, and U. Sonnewald. (2017). Choline transporter-like1 (CHER1) is crucial for plasmodesmata maturation in Arabidopsis thaliana. Plant J. 89: 394-406.
Michel V. and Bakovic M. (2009). The solute carrier 44A1 is a mitochondrial protein and mediates choline transport. FASEB J. 23(8):2749-58.
Nabokina, S.M., V.S. Subramanian, and H.M. Said. (2016). The human colonic thiamine pyrophosphate transporter (hTPPT) is a glycoprotein and N-linked glycosylation is important for its function. Biochim. Biophys. Acta. 1858: 866-871.
Nair T.S., K.E. Kozma, N.L. Hoefling, P.K. Kommareddi, Y. Ueda, T.W. Gong, M.I. Lomax, C.D. Lansford, S.A. Telian, B. Satar, H.A. Arts, H.K. El-Kashlan, W.E. Berryhill, Y. Raphael, T.E. Carey. (2004). Identification and characterization of choline transporter-like protein 2, an inner ear glycoprotein of 68 and 72 kDa that is the target of antibody-induced hearing loss. J Neurosci. 24:1772-1779.
Reuter, M.S., H. Tawamie, R. Buchert, O. Hosny Gebril, T. Froukh, C. Thiel, S. Uebe, A.B. Ekici, M. Krumbiegel, C. Zweier, J. Hoyer, K. Eberlein, J. Bauer, U. Scheller, T.M. Strom, S. Hoffjan, E.R. Abdelraouf, N.A. Meguid, A. Abboud, M.A. Al Khateeb, M. Fakher, S. Hamdan, A. Ismael, S. Muhammad, E. Abdallah, H. Sticht, D. Wieczorek, A. Reis, and R. Abou Jamra. (2017). Diagnostic Yield and Novel Candidate Genes by Exome Sequencing in 152 Consanguineous Families With Neurodevelopmental Disorders. JAMA Psychiatry 74: 293-299.
Taylor, A., S. Grapentine, J. Ichhpuniani, and M. Bakovic. (2021). Choline transporter-like proteins 1 and 2 are newly identified plasma membrane and mitochondrial ethanolamine transporters. J. Biol. Chem. 296: 100604.
Traiffort, E., S. O'Regan, and M. Ruat. (2013). The choline transporter-like family SLC44: properties and roles in human diseases. Mol Aspects Med 34: 646-654.
Yuan Z., L. Wagner, A. Poloumienko, M. Bakovic. (2004). Identification and expression of a mouse muscle-specific CTL1 gene. Gene. 341:305-312.
Yuan, Z., A. Tie, M. Tarnopolsky, and M. Bakovic. (2006). Genomic organization, promoter activity, and expression of the human choline transporter-like protein 1. Physiol Genomics 26: 76-90.
Zirka, G., P. Robert, J. Tilburg, V. Tishkova, C.X. Maracle, P. Legendre, B.J.M. van Vlijmen, M.C. Alessi, P.J. Lenting, P.E. Morange, and G.M. Thomas. (2021). Impaired adhesion of neutrophils expressing Slc44a2/HNA-3b to VWF protects against NETosis under venous shear rates. Blood 137: 2256-2266.
Examples:
TC#	Name	Organismal Type	Example
2.A.92.1.1	The skeletal muscle, Na⁺-dependent, choline transporter-like protein, CTL-1 (SLC44A1; 653 aas) (Yuan et al., 2004) (Present in the plasma membrane, mitochondria and endosomes; catalyzes choline uptake into mitochondria (Michel and Bakovic, 2009).	Eukaryotes	CTL-1 of Mus musculus (Q6X893)

2.A.92.1.10	Choline transporter 1, CHER1, CLT1, SIC1, of 700 aas and 9 TMSs in a 1 + 2 + 2 + 2 + 2 TMS arrangement. It is a choline transporter involved in the regulation of choline metabolite homeostasis during root and phloem development (Dettmer et al. 2014). It is also a regulator of vesicle trafficking, including endocytosis, and is necessary for secondary plasmodesmata (PD) formation and development via the secretory trafficking regulation of proteins required for PD development, thus influencing intercellular communication (Kraner et al. 2017, Gao et al. 2017). It is required for procambium maintenance and sieve plate development (e.g. sieve plate and sieve pore elaboration) to mediate long-distance cell-to-cell communication via symplastic transport through the phloem (Dettmer et al. 2014).		CHER1 of Arabidopsis thaliana

2.A.92.1.2	The inner ear choline transporter-like transporter glycoprotein CLT-2 (CTL2; SLC44A2; 706 aas), target of autoimmune hearing loss (Nair et al., 2004; Kleopa, 2011). CTL2 co-precipitates with multiple isoforms of cochlin (TC# 8.A.54.1.3) which is mutated in individuals with DFNA9 hearing loss (Kommareddi et al. 2007).	Animals	CTL-2 of Homo sapiens (Q8BY89)

2.A.92.1.3	solute carrier family 44, member 3	Animals	SLC44A3 of Homo sapiens

2.A.92.1.4	Choline/ethanolamine transporter-like protein 2, CTL2 (Solute carrier family 44 member 2, SLC44A2) of 706 aas and 9 or 10 TMSs. Slc44A2/HNA-3a is important for the adhesion and activation of neutrophils in veins under inflammation and when submitted to specific shears. The fact that neutrophils expressing Slc44a2/HNA-3b have a different response on von Willebrand factor (VWF) under the conditions tested could explain the association between HNA-3b and a reduced risk for venous thrombosis (VT) in humans (Zirka et al. 2021). See also TC# 2.A.92.1.2 for another human isoform with 91% identity. Protein Msp (Major sheath protein) is a component of the cell surface dentilisin protease complex (TC# 9.B.355.1.1).	Animals	SLC44A2 of Homo sapiens

2.A.92.1.5	Choline transporter-like protein 5 (Solute carrier family 44 member 5)	Animals	SLC44A5 of Homo sapiens

2.A.92.1.6	Choline/ethanolamine transporter, choline transporter-like protein 1 (CTL1; CDW92) (Solute carrier family 44 member 1, SLV44A1) (CD antigen CD92) (Taylor et al. 2021). It transports both choline and ethanolamine (Taylor et al. 2021). The transcriptional regulation and splice variation of the encoding gene have been studied (Yuan et al. 2006). It is found in many tissues including red blood cells (Bryk and Wiśniewski 2017). May be involved in neurodevelopmental disorders (Reuter et al. 2017). CTL1 and CTL2 proteins are present in the plasma membrane and mitochondria, respectively. They have intermediate affinities for choline (Iwao et al. 2016), but it has also been reported that CTL1 has high affinity for ethanolamine while CTL2 has low affinity (Taylor et al. 2021).	Animals	SLC44A1 of Homo sapiens

2.A.92.1.7	Human thiamine pyrophosphate uptake porter, TPPT, a 10 TMS glycoprotein glycosylated on five asparagine residues, some of which are necessary for function (Nabokina et al. 2016). (Solute carrier family 44 member 4).	Animals	SLC44A4 of Homo sapiens

2.A.92.1.8	Protein PNS1 (pH nine-sensitive protein 1)	Fungi	PNS1 of Saccharomyces cerevisiae S288c

2.A.92.1.9	CTL-like protein DDB_G0288717	Amoeba	DDB_G0288717 of Dictyostelium discoideum