9.B.62 The Copper Resistance (CopD) Family The CopD family consists of many homologues with 8 putative TMSs and sizes of about 300 residues from Gram-negative and Gram-positive bacteria. Some homologues from Gram-positive bacteria are larger (Listeria monocytogenes, 541 aas; Corynebacterium efficiens, 356 aas; Streptomyces coelicolor, 680 aas). Some of these proteins are multidomain proteins with extra soluble or membrane integrated domains of unknown function. The E. coli homologue, PcoD, present in an operon (pcoABCDRS), has been characterized from plasmid pRJ1004 (Brown et al., 1995). It is homologous to the CopD protein of Pseudomonas syringae pv. tomato. The proteins in this operon appear to catalyze copper efflux in the logarithmic growth phase but allow accumulation in stationary phase (Brown et al., 1995). Other constituents present in the outer membrane (PcoB) and in the periplasm (PcoA and C) may be involved (Lee et al., 2002; Silver and Ji, 1994). Transcription of pco/cop operons may be controlled by two-component systems such as the PcoS/PcoR sensor kinase/response regulator system. The mechanism of copper resistance is not known but may involve either (1) copper efflux, (2) copper uptake plus periplasmic copper sequestration by CopA and CopC, or (3) copper uptake by a two component CopD-CopC system coupled to an unknown resistance mechanism.
This family belongs to the Copper Resistance (CuR) Superfamily.
References:
Brown, N.L., S.R. Barrett, J. Camakaris, B.T. Lee, and D.A. Rouch. (1995). Molecular genetics and transport analysis of the copper-resistance determinant (pco) from Escherichia coli plasmid pRJ1004. Mol. Microbiol. 17: 1153-1166.
Lee, S.M., G. Grass, C. Rensing, S.R. Barrett, C.J.D. Yates, J.V. Stoyanov, and N.L. Brown. (2002). The Pco proteins are involved in periplasmic copper handling in Escherichia coli. Biochem. Biophys. Res. Commun. 295: 616-620.
Mills, S.D., C.A. Jasalavich, and D.A. Cooksey. (1993). A two-component regulatory system required for copper-inducible expression of the copper resistance operon of Pseudomonas syringae. J. Bacteriol. 175: 1656-1664.
Morosov, X., C.F. Davoudi, M. Baumgart, M. Brocker, and M. Bott. (2018). The copper-deprivation stimulon of comprises proteins for biogenesis of the actinobacterial cytochrome - supercomplex. J. Biol. Chem. 293: 15628-15640.
Rehan, M., T. Furnholm, R.H. Finethy, F. Chu, G. El-Fadly, and L.S. Tisa. (2014). Copper tolerance in Frankia sp. strain EuI1c involves surface binding and copper transport. Appl. Microbiol. Biotechnol. 98: 8005-8015.
Silver, S. and G. Ji. (1994). Newer systems for bacterial resistances to toxic heavy metals. Environ Health Perspect 102Suppl3: 107-113.
Williams, C.L., H.M. Neu, Y.A. Alamneh, R.M. Reddinger, A.C. Jacobs, S. Singh, R. Abu-Taleb, S.L.J. Michel, D.V. Zurawski, and D.S. Merrell. (2020). Characterization of Copper Resistance Reveals a Role in Virulence. Front Microbiol 11: 16.
Examples:
TC#	Name	Organismal Type	Example
9.B.62.1.1	The PcoD copper resistance protein of 309 aas and 8 TMSs.	Gram-negative bacteria	*PcoD of E. coli* (S52256)**

9.B.62.1.2	The CopD copper resistance protein of 310 aas and 8 TMSs.	Gram-negative bacteria	*CopD of Pseudomonas syringae* (P12377)**

9.B.62.1.3	CopD homologue of 296 aas and 8 TMSs	Proteobacteria	CopD of Roseomonas cervicalis

9.B.62.1.4	Uncharacterized membrane protein of 290 aas and 8 TMSs, YebZ.		YebZ of E. coli

9.B.62.1.5	Copper (Cu²⁺) resistance system, CopC (high affinity periplasmic Cu²⁺ binding protein of 122 aas)/CopD (membrane protein of 291 aas and 8 TMSs) (Wijekoon et al. 2015). May function with the periplasmic CopA protein and the outer membrane porin, CopB (see TC# 1.B.76.1.6).		CopCD of Pseudomonas fluorescens

9.B.62.1.6	*CopD or PcoD of 293 aas and 8 TMSs. Involved in copper resistance, probably due to copper efflux and plays a role in virulence (Williams et al.* 2020).**		PcoCD of Acinetobacter baumannii

Examples:
TC#	Name	Organismal Type	Example
9.B.62.2.1	Copper resistance protein, CopC of 559 aas and 10 TMS in a 1 + 9 TMS arrangement.	Actinobacteria	*CopC of Frankia* sp.**

9.B.62.2.2	Copper resistance protein CopCD of 551 aas and 9 TMSs	Actinobacteria	CopCD of Frankia symbiont subsp. Datisca glomerata

9.B.62.2.3	*Copper resistance D domain protein, CopD of 410 aas and 9 TMSs; may function with the periplasmic CopC copper binding protein (Rehan et al.* 2014).**	Actinobacteria	*CopCD of Frankia* sp. strain EuI1c**

9.B.62.2.4	CopCD of 659 aas and 8 TMSs.	Euryarchaea	CopCD of Natronomonas pharaonis

9.B.62.2.5	CopD homologue of 311 aas and 8 TMSs.	Proteobacteria	CopD of Acidiphilium multivorum

9.B.62.2.6	Uncharacterized protein of 157 aas and 4 TMSs.	Proteobacteria	UP of Tistrella mobilis

Examples:
TC#	Name	Organismal Type	Example
9.B.62.3.1	Copper resistance protein, CopD of 736 aas and 16 TMSs in an apparent 8 + 8 TMS arrangement.	Actinobacteria	*CopD of Frankia* sp.**

9.B.62.3.10	CopD/CopC pair of a putative copper transport system. CopD is of 673 aas and 16 putative TMSs; CopC is of 194 aas and 2 TMSs, N- and C-terminal. This system is very similar to that of TC# 9.B.62.3.9 (~50% identical).		CopD/CopC of Corynebacterium glutamicum

9.B.62.3.2	This protein has a cytochrome c oxidase caa3-type, assembly factor CtaG-related C-terminal protein domain (~475 - 725 aas) with an N-terminal CopD/PcoD copper sequestering domain (~150 - 375 aas). The protein is of 767 aas with 16 TMSs.	Actinobacteria	CtaG of Frankia sp.

9.B.62.3.3	Putative copper transporter of 249 aas.	*Deinococcus/Thermus*	Putative copper transporter of Deinococcus radiodurans

9.B.62.3.4	Putative copper transporter of 176 aas and 4 TMSs.	Actinobacteria	Putative copper transporter of Rhodococcus ruber

9.B.62.3.5	Uncharacterized protein of 223 aas and 5 TMSs	Planctomycetes	UP of Rhodopirellula baltica

9.B.62.3.6	CopD of 321 aas and 9 TMSs.	Actinobacteria	CopD of Mycobacterium smegmatis

9.B.62.3.7	CopD of 270 aas and 7 TMSs.	Actinobacteria	copD of Tsukamurella paurometabola

9.B.62.3.8	Uncharacterized protein of 191 aas and 6 TMSs		UP of Sagittula stellata

9.B.62.3.9	CtiP of 701 aas and 16 TMSs. It has an N-terminal domain resembling the CopD-like copper importer of P. syringae and a cytochrome oxidase maturation protein C-terminal domain resembling CtrG of B. subtilis. This protein is required for the biogenesis of the actinobacterial cytochrome bc1-aa3 supercomplex (Morosov et al. 2018).		CtiP of Corynebacterium glutamicum

Examples:
TC#	Name	Organismal Type	Example
9.B.62.4.1	Uncharacterized protein of 303 aas and 7 TMSs	Chloroflexi	UP of Caldilinea aerophila

Examples:
TC#	Name	Organismal Type	Example
9.B.62.5.1	Uncharacterized protein of 150 aas and 4 TMSs	Aquificae	UP of Hydrogenobacter thermophilus

9.B.62.5.2	Uncharacterized protein of 183 aas and 4 TMSs.	Proteobacteria	UP of Komagataeibacter hansenii (Gluconacetobacter hansenii)

9.B.62.5.3	Uncharacterized protein of 153 aas and 3 TMSs	Euryarchaea	UP of Halomicrobium mukohataei (Haloarcula mukohataei)

Examples:
TC#	Name	Organismal Type	Example