scholarly journals Multiple di-leucines in the ATP7A copper transporter are required for retrograde trafficking to the trans-Golgi network

Metallomics ◽  
2016 ◽  
Vol 8 (9) ◽  
pp. 993-1001 ◽  
Author(s):  
Sha Zhu ◽  
Vinit Shanbhag ◽  
Victoria L. Hodgkinson ◽  
Michael J. Petris
Keyword(s):  
Copper Metabolism ◽  
Menkes Disease ◽  
Copper Transporter ◽  
Retrograde Trafficking ◽  
Trans Golgi Network ◽  
P Type ◽  
Golgi Network

The ATP7A protein is a ubiquitous copper-transporting P-type ATPase that is mutated in the lethal pediatric disorder of copper metabolism, Menkes disease.

Identification of a di-leucine motif within the C terminus domain of the Menkes disease protein that mediates endocytosis from the plasma membrane

1999 ◽  
Vol 112 (11) ◽  
pp. 1721-1732 ◽  
Author(s):  
M.J. Francis ◽  
E.E. Jones ◽  
E.R. Levy ◽  
R.L. Martin ◽  
S. Ponnambalam ◽  
...  
Keyword(s):  
Plasma Membrane ◽  
Golgi Apparatus ◽  
Transmembrane Domain ◽  
Menkes Disease ◽  
Cytoplasmic Domain ◽  
Endocytic Pathway ◽  
Site Directed Mutagenesis ◽  
Trans Golgi Network ◽  
C Terminus ◽  
Golgi Network

The protein encoded by the Menkes disease gene (MNK) is localised to the Golgi apparatus and cycles between the trans-Golgi network and the plasma membrane in cultured cells on addition and removal of copper to the growth medium. This suggests that MNK protein contains active signals that are involved in the retention of the protein to the trans-Golgi network and retrieval of the protein from the plasma membrane. Previous studies have identified a signal involved in Golgi retention within transmembrane domain 3 of MNK. To identify a motif sufficient for retrieval of MNK from the plasma membrane, we analysed the cytoplasmic domain, downstream of transmembrane domain 7 and 8. Chimeric constructs containing this cytoplasmic domain fused to the reporter molecule CD8 localised the retrieval signal(s) to 62 amino acids at the C terminus. Further studies were performed on putative internalisation motifs, using site-directed mutagenesis, protein expression, chemical treatment and immunofluorescence. We observed that a di-leucine motif (L1487L1488) was essential for rapid internalisation of chimeric CD8 proteins and the full-length Menkes cDNA from the plasma membrane. We suggest that this motif mediates the retrieval of MNK from the plasma membrane into the endocytic pathway, via the recycling endosomes, but is not sufficient on its own to return the protein to the Golgi apparatus. These studies provide a basis with which to identify other motifs important in the sorting and delivery of MNK from the plasma membrane to the Golgi apparatus.

scholarly journals Ride the wave: Retrograde trafficking becomes Ca2+ dependent with BAIAP3

2017 ◽  
Vol 216 (7) ◽  
pp. 1887-1889 ◽  
Author(s):  
Jakob B. Sørensen
Keyword(s):  
Angiogenesis Inhibitor ◽  
Secretory Vesicle ◽  
Vesicle Formation ◽  
Retrograde Trafficking ◽  
Trans Golgi Network ◽  
Cell Biol ◽  
Golgi Network

The functions of four of the five proteins in the mammalian uncoordinated-13 (Munc13) family have been identified as priming factors in SNARE-dependent exocytosis. In this issue, Zhang et al. (2017. J. Cell Biol. https://doi.org/10.1083/jcb.201702099) show that the fifth member, BAIAP3 (brain-specific angiogenesis inhibitor I–associated protein 3), acts in retrograde trafficking by returning secretory vesicle material to the trans-Golgi network. In its absence, secretory vesicle formation is impaired, leading to accumulation of immature vesicles, or lysosomal vesicle degradation.

IV. Wilson’s disease and Menkes disease

1999 ◽  
Vol 276 (2) ◽  
pp. G311-G314 ◽  
Author(s):  
Mark Schaefer ◽  
Jonathan D. Gitlin
Keyword(s):  
Wilson’S Disease ◽  
Clinical Presentation ◽  
Genetic Disorders ◽  
Copper Metabolism ◽  
Menkes Disease ◽  
Wilson's Disease ◽  
Inherited Disorders ◽  
Specific Expression ◽  
Cellular Copper ◽  
Golgi Network

Copper is an essential transition metal that permits the facile transfer of electrons in a series of critical biochemical pathways. Menkes disease and Wilson’s disease are inherited disorders of copper metabolism resulting from the absence or dysfunction of homologous copper-transporting ATPases that reside in the trans-Golgi network of all cells. Despite striking differences in the clinical presentation of these two diseases, the respective ATPases function in precisely the same manner within the cell and the unique clinical features of each disease are entirely the result of the tissue-specific expression of each protein. Elucidation of the basic defect in these rare genetic disorders has provided a valuable heuristic paradigm for understanding the mechanisms of cellular copper homeostasis.

Metabolic and Molecular Bases of Menkes Disease and Occipital Horn Syndrome

1998 ◽  
Vol 1 (1) ◽  
pp. 85-98 ◽  
Author(s):  
Stephen G. Kaler
Keyword(s):  
Major Gene ◽  
Premature Death ◽  
Menkes Disease ◽  
Pedigree Analysis ◽  
Copper Transport ◽  
Gene Deletions ◽  
Molecular Defects ◽  
P Type ◽  
Golgi Network ◽  
Occipital Horn

Menkes disease and occipital horn syndrome (OHS) are related disorders of copper transport that involve abnormal neurodevelopment, connective tissue problems, and often premature death. Location of the gene responsible for these conditions on the X chromosome was indicated by pedigree analysis from the time of these syndromes' earliest descriptions. Characterization of an affected female with an X-autosomal translocation was used to identify the Menkes/OHS gene, which encodes a highly evolutionarily conserved, copper-transporting P-type ATPase. The gene normally is expressed in nearly all human tissues, and it localizes to the trans-Golgi network of cells. However, in over 70% of Menkes and OHS patients studied, expression of this gene has been demonstrated to be abnormal. Major gene deletions detectable by Southern blotting account for 15–20% of patients, and an interesting spectrum of other mutations is evident among 58 families whose precise molecular defects have been reported as of this writing. The center region of the gene seems particularly prone to mutation, and those that influence mRNA processing and splicing appear to be relatively common. Further advances in understanding the molecular and cell biological mechanisms involved in normal copper transport may ultimately yield new and better approaches to the management of these disorders.

scholarly journals Two forms of Wilson disease protein produced by alternative splicing are localized in distinct cellular compartments

1997 ◽  
Vol 326 (3) ◽  
pp. 897-902 ◽  
Author(s):  
Xiao-Li YANG ◽  
Naoyuki MIURA ◽  
Yoshihiko KAWARADA ◽  
Kunihiko TERADA ◽  
Konstantin PETRUKHIN ◽  
...  
Keyword(s):  
Alternative Splicing ◽  
Wilson Disease ◽  
Intracellular Transport ◽  
Copper Metabolism ◽  
Copper Transporter ◽  
Wilson Disease Protein ◽  
Disease Protein ◽  
Human Disorders ◽  
P Type ◽  
Cellular Compartments

Copper is an essential trace element in prokaryotes and eukaryotes and is strictly regulated by biological mechanisms. Menkes and Wilson diseases are human disorders that arise from disruption of the normal process of copper export from the cytosol to the extracellular environment. Recently a gene for Wilson disease (WD) (also named the ATP7B gene) was cloned. This gene encodes a copper transporter of the P-type ATPase. We prepared monoclonal and polyclonal anti-(WD protein) antibodies and characterized the full-length WD protein as well as a shorter form that is produced by alternative splicing in the human brain. We found that the WD protein is localized mainly in the Golgi apparatus, whereas the shorter form is present in the cytosol. These results suggest that the alternative WD proteins act as key regulators of copper metabolism, perhaps by performing distinct roles in the intracellular transport and export of copper.

scholarly journals Menkes Protein Contributes to the Function of Peptidylglycine α-Amidating Monooxygenase

Endocrinology ◽  
2003 ◽  
Vol 144 (1) ◽  
pp. 188-200 ◽  
Author(s):  
Tami C. Steveson ◽  
Giuseppe D. Ciccotosto ◽  
Xin-Ming Ma ◽  
Gregory P. Mueller ◽  
Richard E. Mains ◽  
...  
Keyword(s):  
Biological Effects ◽  
Menkes Disease ◽  
Copper Zinc Superoxide Dismutase ◽  
Protein Levels ◽  
Brain Extracts ◽  
Copper Zinc ◽  
Menkes Protein ◽  
P Type ◽  
Golgi Network ◽  
Rats And Mice

Abstract Menkes protein (ATP7A) is a P-type ATPase involved in copper uptake and homeostasis. Disturbed copper homeostasis occurs in patients with Menkes disease, an X-linked disorder characterized by mental retardation, neurodegeneration, connective tissue disorders, and early childhood death. Mutations in ATP7A result in malfunction of copper-requiring enzymes, such as tyrosinase and copper/zinc superoxide dismutase. The first step of the two-step amidation reaction carried out by peptidylglycine α-amidating monooxygenase (PAM) also requires copper. We used tissue from wild-type rats and mice and an ATP7A-specific antibody to determine that ATP7A is expressed at high levels in tissues expressing high levels of PAM. ATP7A is largely localized to the trans Golgi network in pituitary endocrine cells. The Atp7a mouse, bearing a mutation in the Atp7a gene, is an excellent model system for examining the consequences of ATP7A malfunction. Despite normal levels of PAM protein, levels of several amidated peptides were reduced in pituitary and brain extracts of Atp7a mice, demonstrating that PAM function is compromised when ATP7A is inactive. Based on these results, we conclude that a reduction in the ability of PAM to produce bioactive end-products involved in neuronal growth and development could contribute to many of the biological effects associated with Menkes disease.

scholarly journals Loss of P4 ATPases Drs2p and Dnf3p Disrupts Aminophospholipid Transport and Asymmetry in Yeast Post-Golgi Secretory Vesicles

2006 ◽  
Vol 17 (4) ◽  
pp. 1632-1642 ◽  
Author(s):  
Nele Alder-Baerens ◽  
Quirine Lisman ◽  
Lambert Luong ◽  
Thomas Pomorski ◽  
Joost C.M. Holthuis
Keyword(s):  
Plasma Membrane ◽  
Cell Surface ◽  
Plasma Membranes ◽  
Atp Hydrolysis ◽  
Budding Yeast ◽  
Secretory Vesicles ◽  
Trans Golgi Network ◽  
P Type ◽  
Golgi Network

Eukaryotic plasma membranes generally display asymmetric lipid distributions with the aminophospholipids concentrated in the cytosolic leaflet. This arrangement is maintained by aminophospholipid translocases (APLTs) that use ATP hydrolysis to flip phosphatidylserine (PS) and phosphatidylethanolamine (PE) from the external to the cytosolic leaflet. The identity of APLTs has not been established, but prime candidates are members of the P4 subfamily of P-type ATPases. Removal of P4 ATPases Dnf1p and Dnf2p from budding yeast abolishes inward translocation of 6-[(7-nitrobenz-2-oxa-1,3-diazol-4-yl)aminocaproyl] (NBD)-labeled PS, PE, and phosphatidylcholine (PC) across the plasma membrane and causes cell surface exposure of endogenous PE. Here, we show that yeast post-Golgi secretory vesicles (SVs) contain a translocase activity that flips NBD-PS, NBD-PE, and NBD-PC to the cytosolic leaflet. This activity is independent of Dnf1p and Dnf2p but requires two other P4 ATPases, Drs2p and Dnf3p, that reside primarily in the trans-Golgi network. Moreover, SVs have an asymmetric PE arrangement that is lost upon removal of Drs2p and Dnf3p. Our results indicate that aminophospholipid asymmetry is created when membrane flows through the Golgi and that P4-ATPases are essential for this process.

scholarly journals Cdc50p, a Protein Required for Polarized Growth, Associates with the Drs2p P-Type ATPase Implicated in Phospholipid Translocation in Saccharomyces cerevisiae

2004 ◽  
Vol 15 (7) ◽  
pp. 3418-3432 ◽  
Author(s):  
Koji Saito ◽  
Konomi Fujimura-Kamada ◽  
Nobumichi Furuta ◽  
Utako Kato ◽  
Masato Umeda ◽  
...  
Keyword(s):  
Transmembrane Protein ◽  
Late Endosome ◽  
Cortical Actin ◽  
Trans Golgi Network ◽  
Polarized Cell Growth ◽  
P Type ◽  
Golgi Network ◽  
Redundant Functions ◽  
Mutant Cells ◽  
Er Membrane

Cdc50p, a transmembrane protein localized to the late endosome, is required for polarized cell growth in yeast. Genetic studies suggest that CDC50 performs a function similar to DRS2, which encodes a P-type ATPase of the aminophospholipid translocase (APT) subfamily. At low temperatures, drs2Δ mutant cells exhibited depolarization of cortical actin patches and mislocalization of polarity regulators, such as Bni1p and Gic1p, in a manner similar to the cdc50Δ mutant. Both Cdc50p and Drs2p were localized to the trans-Golgi network and late endosome. Cdc50p was coimmunoprecipitated with Drs2p from membrane protein extracts. In cdc50Δ mutant cells, Drs2p resided on the endoplasmic reticulum (ER), whereas Cdc50p was found on the ER membrane in drs2Δ cells, suggesting that the association on the ER membrane is required for transport of the Cdc50p-Drs2p complex to the trans-Golgi network. Lem3/Ros3p, a homolog of Cdc50p, was coimmunoprecipitated with another APT, Dnf1p; Lem3p was required for exit of Dnf1p out of the ER. Both Cdc50p-Drs2p and Lem3p-Dnf1p were confined to the plasma membrane upon blockade of endocytosis, suggesting that these proteins cycle between the exocytic and endocytic pathways, likely performing redundant functions. Thus, phospholipid asymmetry plays an important role in the establishment of cell polarity; the Cdc50p/Lem3p family likely constitute potential subunits specific to unique P-type ATPases of the APT subfamily.

Inherited diseases of copper metabolism: Wilson’s disease and Menkes’ disease

2010 ◽  
pp. 1688-1693
Author(s):  
Michael L. Schilsky ◽  
Pramod K. Mistry
Keyword(s):  
Autosomal Recessive ◽  
Copper Metabolism ◽  
Menkes Disease ◽  
Wilson's Disease ◽  
Copper Transport ◽  
Genetic Defects ◽  
Loss Of Function ◽  
Essential Metal ◽  
Inherited Diseases ◽  
P Type

Copper is an essential metal that is an important cofactor for many proteins and enzymes. Two related genetic defects in copper transport have been described. An uncommon disorder (1 in 30 000) caused by autosomal recessive loss of function mutations in a metal-transporting P-type ATPase (...

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