9.A.55 The TMEM205 (TMEM205) Family Development of cisplatin resistance in cancer cells appears to be a consequence of multiple epigenetic alterations in genes involved in DNA damage repair, proto-oncogenes, apoptosis, transporters, transcription factors, etc. Shen et al. (2010) found that expression of the hypothetical transmembrane protein TMEM205 (previously known as MBC3205) is associated with cisplatin resistance. TMEM205 was first detected by functional cloning from a retroviral cDNA library made from human cisplatin-resistant (CP-r) cells. TMEM205 is predicted to be a transmembrane protein. A polyclonal antibody directed to the TMEM205 protein showed that it is located at the cell surface. Stable transfection of the TMEM205 gene confered resistance to cisplatin by approximately 2.5-fold. Uptake assays with Alexa Fluor-cisplatin showed reduced accumulation. Analysis of TMEM205 expression profiles in normal human tissues indicates a differential expression pattern with higher expression levels in the liver, pancreas, and adrenal glands (Shen et al., 2010). The RAB8 protein has been shown to enhance TMEM205-mediated cisplatin resistance (Shen and Gottesman 2012). Further, single nucleotide polymorphisms (SNPs) in the TMEM205 gene alter the efficacy of platinum-based chemotherapy (Wang et al. 2014). These results all indicate that cisplatin resistance is mediated by transport, probably efflux, via TMEM205.
This family belongs to the Copper Resistance (CuR) Superfamily.
References:
Attwood, M.M., A. Krishnan, V. Pivotti, S. Yazdi, M.S. Almén, and H.B. Schiöth. (2016). Topology based identification and comprehensive classification of four-transmembrane helix containing proteins (4TMs) in the human genome. BMC Genomics 17: 268.
Ferraro, G., V. Sanfilippo, L. Chiaverini, C. Satriano, T. Marzo, A. Merlino, and D. La Mendola. (2023). Cisplatin binding to angiogenin protein: new molecular pathways and targets for the drug''s anticancer activity. Dalton Trans. [Epub: Ahead of Print]
Gallenito, M.J., T.S. Qasim, J.N. Tutol, V. Prakash, S.C. Dodani, and G. Meloni. (2020). A recombinant platform to characterize the role of transmembrane protein hTMEM205 in Pt(II)-drug resistance and extrusion. Metallomics 12: 1542-1554.
Heynemann, S., H. Yu, L. Churilov, G. Rivalland, K. Asadi, R. Mosher, F. Hirsch, C. Rivard, and P. Mitchell. (2021). NaPi2b expression in a large surgical Non-Small Cell Lung Cancer (NSCLC) cohort. Clin Lung Cancer. [Epub: Ahead of Print]
Shen, D.W. and M.M. Gottesman. (2012). RAB8 enhances TMEM205-mediated cisplatin resistance. Pharm Res 29: 643-650.
Shen, D.W., J. Ma, M. Okabe, G. Zhang, D. Xia, and M.M. Gottesman. (2010). Elevated expression of TMEM205, a hypothetical membrane protein, is associated with cisplatin resistance. J Cell Physiol 225: 822-828.
Wang, Y., J.Y. Yin, X.P. Li, J. Chen, C.Y. Qian, Y. Zheng, Y.L. Fu, Z.Y. Chen, H.H. Zhou, and Z.Q. Liu. (2014). The association of transporter genes polymorphisms and lung cancer chemotherapy response. PLoS One 9: e91967.
Examples:
TC#	Name	Organismal Type	Example
9.A.55.1.1	The cisplatin (Pt²⁺ coordinatioin complex/ Pt²⁺ drug complexes) exporter, TMEM205; DUF4149. Genetic polymorphisms may alter chemotheraputic responses in lung cancer patients. (Shen et al., 2010; Shen and Gottesman 2012; Wang et al. 2014). The N- and C-termini may be extracellular (Attwood et al. 2016). Human TMEM205 mediates Pt(ii)-drug export selectively towards cisplatin and oxaliplatin but not carboplatin (Gallenito et al. 2020). By mutational analyses, they showed that hTMEM205 recognizes and allows Pt(ii)-extrusion by a putative sulfur-based translocation mechanism, thereby resulting in pre-target resistance. The small endosomal recycling GTPase, RAB8, plays a role in TMEM205-associated resistance to the chemotherapeutic drug cisplatin (Shen and Gottesman 2012). Cisplatin binding to the angiogenin protein provides a new molecular pathway and target for the drug's anticancer activity (Ferraro et al. 2023).	Mammals	*TMEM205 of Homo sapiens* (Q6UW68)**

9.A.55.1.10	Uncharacterized protein of 125 aas and 4 TMSs.	Proteobacteria	UP of Bdellovibrio bacteriovorus

9.A.55.1.11	Uncharacterized protein of 167 aas and 4 TMSs	Acidobacteria	UP of Granulicella mallensis

9.A.55.1.12	Uncharacterized protein of 135 aas and 4 TMSs	Proteobacteria	UP of Glaciecola nitratireducens

9.A.55.1.13	Uncharacterized protein of 165 aas and 4 TMSs	Proteobacteria	UP of Halorhodospira halophila (Ectothiorhodospira halophila)

9.A.55.1.14	Uncharacterized protein of 143 aas and 4 TMSs	Firmicutes	UP of Sulfobacillus acidophilus

9.A.55.1.2	Uncharacterized protein of 171 aas and 4 TMSs	Proteobacteria	UP of Desulfobulbus propionicus

9.A.55.1.3	DUF4149 protein of 155 aas and 4 TMSs	Proteobacteria	DUF4149 protein Ralstonia pickettii

9.A.55.1.4	Uncharacterized protein of 295 aas and 5 or 6 TMSs in a 2 + 2 + 1 TMS arrangement, possibly with another TMS towards the C-terminus of the 110 aa N-terminal hydrophilic alanine-rich domain.	Algae	UP of Chlamydomonas reinhardtii (Chlamydomonas smithii)

9.A.55.1.5	Uncharacterized protein of 167 aas and 4 TMSs.	Aquificae	UP of Sulfurihydrogenibium azorense

9.A.55.1.6	Uncharacterized protein of 179 aas and 4 TMSs.	Nitrospirae	UP of Leptospirillum ferrodiazotrophum

9.A.55.1.7	Uncharacterized protein of 170 aas and 4 TMSs.	Verucomicrobia	UP of Pedosphaera parvula

9.A.55.1.8	Uncharacterized protein of 158 aas and 4 TMSs.	Armatimonadetes	UP of Chthonomonas calidirosea

9.A.55.1.9	Uncharacterized DUF4149 protein of 147 aas and 4 TMSs.	Bacteroidetes	UP of Psychroflexus gondwanensis

Examples:
TC#	Name	Organismal Type	Example
9.A.55.2.1	Uncharacterized protein of 186 aas and 4 TMSs	Fungi	*UP of Leptosphaeria maculans* (Blackleg fungus) (Phoma lingam)**

9.A.55.2.2	Uncharacterized protein of 208 aas and 4 TMSs.	Fungi	UP of Wallemia sebi

Examples:
TC#	Name	Organismal Type	Example
9.A.55.3.1	Uncharacterized protein of 169 aas and 4 TMSs.	Cyanobacteria	UP of Coleofasciculus chthonoplastes

Examples:
TC#	Name	Organismal Type	Example