User:Daamoy/sandbox: Difference between revisions

The ''ATP7A'' gene is located on the long (q) arm of the [[X chromosome]] between at position 13.3. The encoded ATP7A protein has 1,500 amino acids.<ref name="6.Molecular genetics and pathophysiology of MD">{{cite journal|last1=Kodama|first1=H|last2=Murata|first2=Y|title=Molecular genetics and pathophysiology of Menkes disease.|journal=Pediatrics international : official journal of the Japan Pediatric Society|date=August 1999|volume=41|issue=4|pages=430-5|pmid=10453200}}</ref> Genetic disorder of this gene causes copper deficiency, which leads to progressive neurodegeneration and death in children.<ref>{{cite namejournal|last1="2Kaler|first1=Stephen G.|title=ATP7A-related copper transport diseases"diseases—emerging concepts and future trends|journal=Nature Reviews Neurology|date=January 2011|volume=7|issue=1|pages=15–29|doi=10.1038/nrneurol.2010.180}}</ref>

* A large N-terminal cytosolic domain that contains six tandemly repeated copper-binding sites of about 30 amino acids, each containing a GMTCXXC motif.<ref name="5.Cellular multitasking: The dual role">{{cite journal|last1=Lutsenko|first1=Svetlana|last2=Gupta|first2=Arnab|last3=Burkhead|first3=Jason L.|last4=Zuzel|first4=Vesna|title=Cellular multitasking: The dual role of" human Cu-ATPases in cofactor delivery and intracellular copper balance|journal=Archives of Biochemistry and Biophysics|date=August 2008|volume=476|issue=1|pages=22–32|doi=10.1016/j.abb.2008.05.005}}</ref><ref name="1.Copper-related diseases: From chemistry">{{cite journal|last1=Crisponi|first1=Guido|last2=Nurchi|first2=Valeria Marina|last3=Fanni|first3=Daniela|last4=Gerosa|first4=Clara|last5=Nemolato|first5=Sonia|last6=Faa|first6=Gavino|title=Copper-related diseases: From chemistry to molecular pathology"|journal=Coordination Chemistry Reviews|date=April 2010|volume=254|issue=7-8|pages=876–889|doi=10.1016/j.ccr.2009.12.018}}</ref><ref name=Text1"Textbook NEW">{{cite book|last1=Bertini|first1=Ivano|last2=Gray|first2=Harry|last3=Stiefel|first3=Edward|last4=Valentine|first4=Joan|title=Biological inorganic chemistry : structure and reactivity.|date=2006|publisher=University Science Books|location=Sausalito, CA|isbn=978-1-891389-43-6}}</ref>

Many motifs in the ATP7A structure are conserved, such as the TGEA, CPC, DKTG, SEHPL, and GDGXND motifs. The TGEA motif lies in the loop on the cytosolic side between transmembrane segments 4 and 5 and is involved in energy transduction. The CPC motif located in transmembrane segment 6 is common for all heavy metal transporting ATPases. Between transmembrane segments 6 and 7 is a large cytoplasmic loop, where three motifs are located: DKTG, SEHPL, and GDGXND. The DKTG motif is essential for the proper function of the ATPase. The [[aspartic acid]] (D) residue is phosphorylated during the transport cycles. The SEHPL motif only exists in heavy metal transporting P-type ATPases. Without the [[histidine]] (H) residue ATP7A may not function properly. The GDGXND motif near transmembrane segment 7 is thought to contain mainly α-helices and serves as a structural support.<ref name=Text1"Textbook NEW" />

The six copper-binding sites at the N-terminal bind one Cu per binding site. This binding site is not specific for Cu and can bind various transition metal ions, depending on the identity of the metal ion. Cd(II), Au(III) and Hg(II) binds to the binding site more tightly than does Zn(II), whereas Mn(II) and Ni(II) have lower affinities than relative to Zn(II). In the case of Cu, a possible cooperative-binding mechanism is observed. When the Cu concentration is low, Cu has a lower affinity for ATP7A compared to Zn(II); as the Cu concentration increases, a dramatic increasing affinity of Cu for the protein is observed.<ref name=Text1"Textbook NEW" />

The two [[cysteine]] (C) residues in each copper-binding site are coordinated to Cu(I) with a S-Cu-S angle between 120 and 180° and a Cu-S distance of 2.16 Å. Experimental results from a homologous protein ATP7B suggests that upon Cu binding, the disulfide bonding between the cysteine residues is broken as cysteine starts to bind to Cu, leading to a series of conformational changes at the N-terminal of the protein, and possibly activating the Cu-transporting activity of other cytosolic loops.<ref name=Text1"Textbook NEW" />

Of the six copper-binding sites, two are considered enough for the function of Cu transport. The reason why there are six binding sites remains not fully understood. However, some scientists have proposed that the other four sites may serve as a Cu concentration detector.<ref name="5. Cellular multitasking: The dual roleof" />

ATP7A belongs to a transporter family called [[P-type ATPase|P-type ATPases]], which catalyze auto-[[phosphorylation]] of a key conserved [[aspartic acid]] (D) residue within the enzyme. The first step is ATP binding to the ATP-binding domain and Cu binding to the transmembrane region. Then ATP7A is phosphorylated at the key [[aspartic acid]] (D) residue in the highly conserved DKTG motif, accompanied by Cu release. A subsequence dephosphorylation of the intermediate finishes the catalytic cycle. Within each cycle, ATP7A interconverts between at least two different conformations, E1 and E2. In the E1 state, Cu is tightly bound to the binding sites on the cytoplasmic side; in the E2 state, the affinity of ATP7A for Cu decreases and Cu is released on the extracellular side.<ref name="4. Cellular copper distribution: a mechanistic">{{cite journal|last1=Banci|first1=Lucia|last2=Bertini|first2=Ivano|last3=Cantini|first3=Francesca|last4=Ciofi-Baffoni|first4=Simone|title=Cellular copper distribution: a mechanistic systems biology approach"|journal=Cellular and Molecular Life Sciences|date=24 March 2010|volume=67|issue=15|pages=2563–2589|doi=10.1007/s00018-010-0330-x}}</ref>

ATP7A is important for regulating copper levels in mammals.<ref name="1. Copper-related diseases: From chemistry to molecular pathology" /> This protein is found in most tissues, but it is not expressed in the liver.<ref name=Text1"Textbook NEW" /> In the small intestine, the ATP7A protein helps control the absorption of copper from food. After cupper ions are absorbed into enterocytes, ATP7A is required to transfer them across the basolateral membrane into the circulation.<ref name="5. Cellular multitasking: The dual roleof" />

In other organs and tissues, the ATP7A protein has a dual role and shuttles between two locations within the cell. The protein normally resides in a cell structure called the [[Golgi apparatus]], which modifies and transports newly produced enzymes and other proteins. Here, the ATP7A protein supplies copper to certain enzymes (e.g. [[Peptidylglycine monooxygenase|peptidyl-α-monooxygenase]], [[tyrosinase]], and [[lysyl oxidase]]<ref name="5. Cellular multitasking: The dual roleof" />) that are critical for the structure and function of brain, bone, skin, hair, connective tissue, and the nervous system. If copper levels in the cell environment are elevated, however, the ATP7A protein moves to the cell membrane and eliminates excess copper from the cell.<ref name="1. Copper-related diseases: From chemistry to molecular pathology" /><ref name="2. ATP7A-related copper transport diseases —emerging">{{cite journal|last1=Kaler|first1=Stephen G.|title=ATP7A-related copper transport diseases—emerging concepts and future trends|journal=Nature Reviews Neurology|date=January 2011|volume=7|issue=1|pages=15–29|doi=10.1038/nrneurol.2010.180}}</ref>

The functions of ATP7A in some tissues of the human body are as follows:<ref name="1. Copper-related diseases: From chemistry to molecular pathology" />

ATP7A has been shown to interact with [[ATOX1]] and [[GLRX]]. [[ATOX1|Antioxidant 1 copper chaperone]] (ATOX1) is required to maintain proper copper homeostasis in the cell. It can bind and transport cytosolic copper to ATP7A in the trans-Golgi-network. [[GLRX|Glutaredoxin-1]] (GRX1) has is also essential for ATP7A function. It promotes copper binding for subsequent transport by catalyzing the reduction of disulfide bridges. It may also catalyze de-[[S-glutathionylation|glutathionylation]] reaction of the C (cysteine) residues within the six copper-binding motifs GMTCXXC.<ref name="1. Copper-related diseases: From chemistry to molecular pathology" />

The altered proteins that result from ATP7A mutations impair the absorption of copper from food, fail to supply copper to certain enzymes, or get stuck in the cell membrane, unable to shuttle back and forth from the Golgi. As a result of the disrupted activity of the ATP7A protein, copper is poorly distributed to cells in the body. Copper accumulates in some tissues, such as the small intestine and kidneys, while the brain and other tissues have unusually low levels.<ref name="2.ATP7A-related copper transport diseases" /><ref name="5. Cellular multitasking: The dual role of" /> The decreased supply of copper can reduce the activity of numerous copper-containing enzymes that are necessary for the structure and function of bone, skin, hair, blood vessels, and the nervous system.<ref name="1. Copper-related diseases: From chemistry to molecular pathology" /><ref name="2.ATP7A-related copper transport diseases" />