4 April 2013

The Wilson’s disease protein 29 Wilson’s disease Cu (ATP7B) is a good example of a and the copper ATPase conserved copper transporting 63.546 protein. It is an ATP-driven transporters copper pump that regulates copper By Hsin-Yu Chang and Alex Mitchell homeostasis. Defects in human ATP7B cause InterProProtein Focus an accumulation of copper, since the is In the American TV series House, episode unable to excrete the metal into the bile ‘The Socratic Method’, a mother seeming to (Figure 1). suffer from schizophrenia is admitted to hospital. Her symptoms include hallucinations ‘Since excess copper is toxic, several and liver malfunction. As usual, her condition copper binding/transporting proteins is a puzzle for House’s team, until the have evolved and are preserved throughout evolution.’ eventual ‘Eureka moment’. The team solves the mystery through an eye examination. The InterPro database houses a wide variety Kayser-Fleischer rings (copper-coloured of information on protein families and circles in the cornea) are found in her eyes, domains. Examining the database, fitting the diagnosis of Wilson’s disease - a information on the Wilson’s disease protein genetic disorder in which copper accumulates and its homologues can be found in InterPro in tissue (mainly in the liver and ). entries IPR001757 and its child entry IPR027256 (Table 1). From the description of IPR001757 , we know that ATP7B belongs to a broad family of membrane proteins that translocate ions across cellular membranes,

using the created by ATP hydrolysis 2. Kayser-Fleischer ring Transmembrane are classified into different types according to their functions, For most forms, copper is an essential structures and the type of ions they transport. element. It is utilised by a variety of ATP7B is a Cu+ transporting ATPase, which that play important roles in energy generation, belongs to the IB subfamily of P-type oxygen transport and signal transduction. ATPases (IPR027256) that is made up of Since excess copper is toxic, several copper ATPases involved in transporting Cu+, Ag+, binding/transporting proteins that help 2+ 2+ 2+ 2+ 2+ maintain the copper balance within cells have Zn , Cd , Co , Cu and Pb ions. evolved, and are preserved throughout Family members are found in , and eukaryotes. evolution 1.

1 InterPro Protein Focus 4 April 4 2013 Domain Domain Domain Family Family Entry type Entry Site related entries. related Table P-type “cation-transporting represent that in InterPro 1. Entries ATPase” its and 185 (2008) 185 Cu excess 1. Figure A Cu the shows model D D S D F F InterPro InterPro ID IPR018303 IPR023299 IPR008250 IPR006121 IPR027256 IPR001757 + 2 into the bile. Figure modified from Kimmodified bile. Figure the into . Cation-transporting P-type ATPase, subfamily ATPase, P-type Cation-transporting domain of ATP7B domain (HMA) metal-associated Heavy Cytoplasmic vesicle Cytoplasmic P-type ATPase, cytoplasmic domain N domain cytoplasmic ATPase, P-type Heavy metal-associated domain, HMA domain, metal-associated Heavy P-type ATPase, site phosphorylation ATPase, P-type canaliculus Cation-transporting P-type ATPase P-type Cation-transporting Bile P-type ATPase, A domain ATPase, P-type Entry Name Entry + transporting P-type P-type transporting ATPase, ATP7B, excretes that IB et et al ., Nature Chemical Biology 4, 176 - 4, 176 Biology Chemical ., Nature G3DSA:2.70.150.10 G3DSA:3.40.111 PTHR24093 Copper chaperone Copper ATP7B of domain Transmembrane TIGR01525 TIGR01494 Signatures SSF55008 SSF81660 PR00941 PR00120 PR00119 PS50846 PS00154 PF00122 PF00403 0.10 UniProt Matches ~16898 ~37163 ~39433 ~21387 ~43205 ~37529 Protein NH2 Structure Protein PDB 1jww 2arf 2kij 2 InterPro Protein Focus 4 April 4 2013 the number of HMA domains can vary. For vary. can of HMA domains number the but to humans, from bacteria conserved are domains functional major three the that see can we species, different across homologues ATP7B to compare InterPro Using found be can by (described site phosphorylation conserved a In addition, IPR023299 ( N domain the while function, ( the domain, metal-binding A domain ( domain (actuate) (HMA), the domain metal-associated A domains: functional major of three consists that structure resolved family member related ATP7A been have of structures The ATP7B closely- the and described by described Homo sapiens Homo sapiens Homo S. cerevisiae Oryza sativa Oryza A. thaliana A. thaliana Japonica Species subsp. E. coli described by described 3,4,5,6 domain and the N domain. N domain. the and domain The ) is involved in nucleotide binding. in nucleotide ) is involved N domain, ATP binding (HAD like domain ) domain like (HAD ATP binding N domain, Heavy metal associated (HMA) domain metal associated Heavy in all the P-type P-type in all the ATPases IPR018303 IPR008250 Table 2. Information about ATP7B and some of its homologues. some ATP7B and about 2. Information Table . similar a share They Accession Q9SH30 Q6H6Z1 Q9S7J8 Q04656 Q59385 P35670 P38995 the N-terminal heavy N-terminal the IPR006121 ) is present, which ) is present, regulatory a ) has described by described Uncharacterised ) ) is the HMA7/RAN1 ATP7B ATP7A HMA5 Name CopA Ccc2 . HMA potential function of this protein. We protein. of this function potential it see can the into to drill further us allow entries InterPro IPR001757 type ATPase family, to its matches on based P- the of the IB of the subfamily member is a entry (UniProt protein uncharacterised an that suggests database the example, For characterised. experimentally been yet not have that of proteins function the to predict used be also can InterPro 2). (Table six ATP7B has while have only yeast budding from CopA instance, found in found ATP7B) involved is specifically that HMA of the subclass particular (also domain type ATPase a IB including family members, P- of other typical organisation domain a has functions of uncharacterised proteins’ of functions ‘InterPro can be used to predictthe to used canbe ‘InterPro Domain organisation and Q6H6Z1 IPR027256 A (actuate) domain A (actuate) E. coli ) from short grain rice grain from short two HMAtwo domains, . Matches to other . Matches and Ccc2 from Ccc2 and Length Length (aa) 1002 1001 1465 1500 1004 995 834 3 InterPro Protein Focus 4 April 4 2013 ethylene signalling ethylene in involved receptors hormone functional to create copper delivers which HMA7/RAN1, in homologues their as such Arabidopsis, to similar a function have identified proteins the whether and accurate are predictions if InterPro’s to know willinteresting be It of plant. species in this proteins transporting copper study and to identify is important affect can and production crop toxic is often in rice of copper Accumulation database. InterPro to the similar matches as transporting copper ATPases fromsuch rice, Wilson’s protein. disease potential Additional transporting copper is a ATPase, similar to the Q6H6Z1 protein that likely seems It therefore (see ions copper binding 2. 2. Kim Nat BE, regulation. and distribution Nevitt T,acquisition, for Thiele DJ. copper Mechanisms organisms. eukaryotic in ATPases transporting copper of Evolution S. Lutsenko and A Gupta 1. References 6. 6. Dmitriev O, Tsivkovskii R, Abildgaard F, Morgan CT, Markley JL, Lutsenko S. Solution structure the of structures Solution A. Rosato F, Nushi G, Natile M, Migliardi F, Cantini I, Bertini L, Banci 5. 4. Banci L, Bertini I, Cantini F, Rosenzweig AC, Yatsunyk LA. Metal binding domains 3 and 4 of the 3. Argüello JM, Eren E, González-Guerrero M. The structure and function of heavy metal transport Biochemistry. 47(28):7423-9. 2008 [PMID: 2008 47(28):7423-9. Biochemistry. HAH1. chaperone copper(I) the with interaction and structure solution protein: disease Wilson [PMID: 2007 20(3-4):233-48. Biometals. P1B-ATPases. [PMID: 2008 Biol. Chem 4(3):176-85. A3AWA4 Curr Genomics. 13 (2): 124-33. 2012 [PMID: 2012 124-33. (2): 13 Genomics. Curr of disease . Proc Natl Acad Sci U S A. 103(14):5302-7. 2006 [PMID: 2006 Sci U S A. Natl Acad 103(14):5302-7. Proc mutations. of disease effects and environment nucleotide-binding distinct protein: disease Wilson of N-domain the of [PMID: 2009 48(33):7849-55. actuator domain of ATP7A and ATP7B, the Menkes and Wilson disease proteins. Biochemistry. , can also be predicted, based on based predicted, be also , can 8 . IPR006122 7 . it Therefore 19645496 ). 18277979 ]. 18558714 23024604 ]. serve as a useful tool to help researchers to help tool useful a as serve can databases, with its member together patient’sa to diagnose upon InterPro, illness, calls House Gregory Dr tests clinical the Like pumps. of copper of action mechanisms the on information useful provided and function their underlie that domains the revealed has proteins of these study homeostasis. ion copper maintaining The in roles important all play to humans bacteria (ATP7B)protein from its homologues and Wilson’s the that It is fascinating disease them to 'Eureka moments’ to 'Eureka them own. of their guiding hopefully functions, their identify new potential spot ATP7B and homologues ‘Accumulation of copper in rice in is copper of ‘Accumulation ]. often toxic and canaffect and toxic often crop ]. 17219055 production’ ]. 16567646 ]. 4 4 April 2013

7. Yan YP, He JY, Zhu C, Cheng C, Pan XB, Sun ZY. Accumulation of copper in brown rice and effect of copper on rice growth and grain yield in different rice cultivars. Chemosphere. 65(10):1690-6. 2006 [PMID: 16844189]. 8. Hirayama T, Kieber JJ, Hirayama N, Kogan M, Guzman P, Nourizadeh S, Alonso JM, Dailey WP, Dancis A, Ecker JR. RESPONSIVE-TO-ANTAGONIST1, a Menkes/Wilson disease-related copper transporter, is required for ethylene signaling in Arabidopsis. . 97(3):383-93. 1999 InterProProtein Focus [PMID:10319818].

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