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ATP7A Membrane Protein Introduction

Introduction of ATP7A

ATP7A is a copper-transporting P-type ATPase which plays a role in copper transport across membranes using the energy arising from ATP hydrolysis. ATP7A is localized to the trans-Golgi network, where it is predicted to supply copper to copper-dependent enzymes in the secretory pathway. It delocalizes to the plasma membrane if extracellular copper is elevated, and functions in the copper efflux from cells. Single-nucleotide polymorphism in ATP7A gene is associated with X-linked distal spinal muscular atrophy, Menkes disease, and occipital horn syndrome.

Basic Information of ATP7A
Protein Name Copper-transporting ATPase 1
Gene Name ATP7A
Aliases Copper pump 1, Menkes disease-associated protein
Organism Homo sapiens (Human)
UniProt ID Q04656
Transmembrane Times 8
Length (aa) 1500
Sequence MDPSMGVNSVTISVEGMTCNSCVWTIEQQIGKVNGVHHIKVSLEEKNATIIYDPKLQTPKTLQEAIDDMGFDAVIHNPDPLPVLTDTLFLTVTASLTLPWDHIQSTLLKTKGVTDIKIYPQKRTVAVTIIPSIVNANQIKELVPELSLDTGTLEKKSGACEDHSMAQAGEVVLKMKVEGMTCHSCTSTIEGKIGKLQGVQRIKVSLDNQEATIVYQPHLISVEEMKKQIEAMGFPAFVKKQPKYLKLGAIDVERLKNTPVKSSEGSQQRSPSYTNDSTATFIIDGMHCKSCVSNIESTLSALQYVSSIVVSLENRSAIVKYNASSVTPESLRKAIEAVSPGLYRVSITSEVESTSNSPSSSSLQKIPLNVVSQPLTQETVINIDGMTCNSCVQSIEGVISKKPGVKSIRVSLANSNGTVEYDPLLTSPETLRGAIEDMGFDATLSDTNEPLVVIAQPSSEMPLLTSTNEFYTKGMTPVQDKEEGKNSSKCYIQVTGMTCASCVANIERNLRREEGIYSILVALMAGKAEVRYNPAVIQPPMIAEFIRELGFGATVIENADEGDGVLELVVRGMTCASCVHKIESSLTKHRGILYCSVALATNKAHIKYDPEIIGPRDIIHTIESLGFEASLVKKDRSASHLDHKREIRQWRRSFLVSLFFCIPVMGLMIYMMVMDHHFATLHHNQNMSKEEMINLHSSMFLERQILPGLSVMNLLSFLLCVPVQFFGGWYFYIQAYKALKHKTANMDVLIVLATTIAFAYSLIILLVAMYERAKVNPITFFDTPPMLFVFIALGRWLEHIAKGKTSEALAKLISLQATEATIVTLDSDNILLSEEQVDVELVQRGDIIKVVPGGKFPVDGRVIEGHSMVDESLITGEAMPVAKKPGSTVIAGSINQNGSLLICATHVGADTTLSQIVKLVEEAQTSKAPIQQFADKLSGYFVPFIVFVSIATLLVWIVIGFLNFEIVETYFPGYNRSISRTETIIRFAFQASITVLCIACPCSLGLATPTAVMVGTGVGAQNGILIKGGEPLEMAHKVKVVVFDKTGTITHGTPVVNQVKVLTESNRISHHKILAIVGTAESNSEHPLGTAITKYCKQELDTETLGTCIDFQVVPGCGISCKVTNIEGLLHKNNWNIEDNNIKNASLVQIDASNEQSSTSSSMIIDAQISNALNAQQYKVLIGNREWMIRNGLVINNDVNDFMTEHERKGRTAVLVAVDDELCGLIAIADTVKPEAELAIHILKSMGLEVVLMTGDNSKTARSIASQVGITKVFAEVLPSHKVAKVKQLQEEGKRVAMVGDGINDSPALAMANVGIAIGTGTDVAIEAADVVLIRNDLLDVVASIDLSRETVKRIRINFVFALIYNLVGIPIAAGVFMPIGLVLQPWMGSAAMAASSVSVVLSSLFLKLYRKPTYESYELPARSQIGQKSPSEISVHVGIDDTSRNSPKLGLLDRIVNYSRASINSLLSDKRSLNSVVTSEPDKHSLLVGDFREDDDTAL

Function of ATP7A Membrane Protein

Known as Menkes' protein (MNK), ATP7A is a type of copper-transporting P-type ATPase which can catalyze the hydrolysis of ATP along with the transport of Cu(I) across plasma membranes. ATP7A is expressed in the intestine and almost all tissues except liver. In the intestine, ATP7A mediates Cu(I) absorption in the human body by transporting Cu(I) from the small intestine into the blood. In other tissues, ATP7A translocates between the cell membrane and the Golgi apparatus to control proper Cu(I) concentrations in the cell and supports enzymes with Cu(I) (e.g. lysyl oxidase, tyrosinase, and peptidyl-α-monooxygenase), that are critical for the structures and functions of brain, bone, connective tissue and the nervous system. Single-nucleotide polymorphism of the ATP7A can lead to Menkes disease (MD), which is inherited and X-linked and can result in early childhood death for a copper deficiency. There is no experiment structure of ATP7A available in PDB. Below is a schematic diagram of the ATP7A (Fig.1).

Schematic diagram of the copper-ATPases, ATP7A. Fig.1 Schematic diagram of the copper-ATPases, ATP7A.

Application of ATP7A Membrane Protein in Literature

  1. Møller L.B., et al. Small amounts of functional ATP7A protein permit mild phenotype. J Trace Elem Med Biol. 2015, 31:173-7. PubMed ID: 25172213

    This article confirms that ATP7A locates to the Trans-Golgi Network (TGN) to load cuproenzymes with copper at low copper levels, but shifts to the plasma membrane or to the post-Golgi compartments to export copper out of the cell at higher copper concentrations. On the other hand, ATP7A mutants have been found able to impair copper-regulation trafficking.

  2. Tümer Z., et al. An overview and update of ATP7A mutations leading to Menkes disease and occipital horn syndrome. Hum Mutat. 2013, 34(3): 417-29. PubMed ID: 23281160

    This article reviews 18 novel and 274 published disease-causing mutations identified in 370 unrelated Menkes disease patients, nonpathogenic variants of ATP7A, functional studies of the ATP7A mutations, and animal models of Menkes disease.

  3. Kaler S.G., et al. ATP7A-related copper transport diseases-emerging concepts and future trends. Nat Rev Neurol. 2011, 7(1): 15-29. PubMed ID: 21221114

    This article indicates that ATP7A has a significant but previously unappreciated function in motor neuron maintenance, and that the mechanism underlying ATP7A-related distal motor neuropathy is distinct from Menkes disease and OHS pathophysiology.

  4. Cheung B.B., et al. Targeting ATP7A to increase the sensitivity of neuroblastoma cells to retinoid therapy. Curr Cancer Drug Targets. 2011, 11(7): 826-36. PubMed ID: 21762080

    This article suggests that strategies targeting the copper export protein, ATP7A, may have great therapeutic potential in the clinical treatment of neuroblastoma and other malignancies, in combination therapy with retinoids and copper depletion therapy.

  5. Lenartowicz M and Krzeptowski W., et.al. Structure and function of ATP7A and ATP7B proteins-Cu-transporting ATPases. Postepy Biochem. 2010, 56(3): 317-27. PubMed ID: 21117320

    This article confirms that the loss of ATP7A and ATP7B functions caused by single-nucleotide polymorphism may contribute to severe metabolic diseases Menkes and Wilson diseases, respectively.

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Reference

  1. Patat, et al. (2016). Truncating mutations in the adhesion G protein-coupled receptor G2 gene ATP7A cause an X-linked congenital bilateral absence of vas deferens. The American Journal of Human Genetics. 99(2): 437-442.

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