ER_Stress_stable.xml 1020 KB
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<?xml version="1.0" encoding="UTF-8"?>
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<sbml xmlns="http://www.sbml.org/sbml/level2/version4" xmlns:celldesigner="http://www.sbml.org/2001/ns/celldesigner" xmlns:xsi="http://www.w3.org/2001/XMLSchema-instance" level="2" version="4">
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<model metaid="CDMT00001">
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<notes>
<html xmlns="http://www.w3.org/1999/xhtml">
<head>
<title/>
</head>
<body>
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  Authors:
  Luis Cristobal Monraz Gomez, Inna Kuperstein, Institut Curie
  Barbara Brauner, Andreas Ruepp, Helmholtz Zentrum München / Institute of Experimental Genetics, Germany
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<br/>
<br/>
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  DESCRIPTION:
  This diagram depicts the activity of the Unfolded Protein Response (UPR) that leads to endoplasmic reticulum stress and further apoptosis.
  During the Sars-CoV-2 infection, this mechanism is activated in the infected cells of the host.
  Mitochondria-Assoociated Membranes (MAMs) are also featured, showing the impact on mitochondria and calcium homeostasis
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</body>
</html>
</notes>
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<annotation>
<celldesigner:extension>
<celldesigner:modelVersion>4.0</celldesigner:modelVersion>
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<celldesigner:modelDisplay sizeX="4765" sizeY="2396"/>
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<celldesigner:listOfIncludedSpecies>
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<celldesigner:species id="s_id_path_0_sa181" name="BAX">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
<head>
<title/>
</head>
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa181">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa20</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa181</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa183" name="ERN1">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
<head>
<title/>
</head>
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa183">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa20</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa183</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa25" name="ERN1">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa25">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa6</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa25</celldesigner:proteinReference>
<celldesigner:state>
<celldesigner:homodimer>2</celldesigner:homodimer>
<celldesigner:listOfModifications>
<celldesigner:modification residue="rs1" state="phosphorylated"/>
</celldesigner:listOfModifications>
</celldesigner:state>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa205" name="TRAF2">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa205">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa6</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa205</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa616" name="Unfolded_space_protein">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa616">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa6</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa616</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_1_sa10" name="SIGMAR1">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_1_sa10">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_1_csa14</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_1_sa10</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_1_sa170" name="ITPR3">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_1_sa170">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_1_csa14</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_1_sa170</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa198" name="EIF2AK3">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa198">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa21</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_0_sa198</celldesigner:proteinReference>
<celldesigner:state>
<celldesigner:homodimer>2</celldesigner:homodimer>
<celldesigner:listOfModifications>
<celldesigner:modification residue="rs1" state="phosphorylated"/>
<celldesigner:modification residue="rs2" state="phosphorylated"/>
</celldesigner:listOfModifications>
</celldesigner:state>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_0_sa319" name="ATP">
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<celldesigner:notes>
<html xmlns="http://www.w3.org/1999/xhtml">
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
<rdf:Description rdf:about="#s_id_path_0_sa319">
<dcterms:modified rdf:parseType="Resource"/>
</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa35</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
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<celldesigner:class>SIMPLE_MOLECULE</celldesigner:class>
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<celldesigner:name>ATP</celldesigner:name>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
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<celldesigner:species id="s_id_path_0_sa615" name="EIF2AK4">
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<celldesigner:notes>
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
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</rdf:Description>
</rdf:RDF>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_0_csa35</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
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<celldesigner:class>PROTEIN</celldesigner:class>
<celldesigner:proteinReference>p_s_id_path_0_sa615</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
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</celldesigner:species>
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<celldesigner:species id="s_id_path_1_sa11" name="ITPR3">
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<celldesigner:notes>
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
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</rdf:Description>
</rdf:RDF>
</body>
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</html>
</celldesigner:notes>
<celldesigner:annotation>
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<celldesigner:complexSpecies>s_id_path_1_csa2</celldesigner:complexSpecies>
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<celldesigner:speciesIdentity>
<celldesigner:class>PROTEIN</celldesigner:class>
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<celldesigner:proteinReference>p_s_id_path_1_sa11</celldesigner:proteinReference>
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</celldesigner:speciesIdentity>
</celldesigner:annotation>
</celldesigner:species>
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<celldesigner:species id="s_id_path_1_sa12" name="HSPA9">
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<celldesigner:notes>
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<body>
<rdf:RDF xmlns:bqbiol="http://biomodels.net/biology-qualifiers/" xmlns:bqmodel="http://biomodels.net/model-qualifiers/" xmlns:dc="http://purl.org/dc/elements/1.1/" xmlns:dcterms="http://purl.org/dc/terms/" xmlns:rdf="http://www.w3.org/1999/02/22-rdf-syntax-ns#" xmlns:vCard="http://www.w3.org/2001/vcard-rdf/3.0#">
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BiP(= GRP78 = HSPA5) has a dual function, in addition to its chaperone role it is a bona fide ER lumenal Ca2+ storage protein contributing, under resting cell conditions, to around 25% of the store, with a stoichiometry of 1-2 moles of calcium/mole of BiP. Thus, playing an important role in the control of the ER lumenal Ca2+ homeostasis (PMID:9388233).
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Mfn2 but not Mfn1 is an ER stress-inducible protein that is required for the proper temporal sequence of the ER stress response (PMID:22511781).
MFN2 regulates shape of the ER and tethers it to mitochondria, by engaging in homo- and hetero-complexes comprising MFN2 at the ER and MFN2 or MFN1 on mitochondria. Ablation or silencing of mitofusin 2 in mouse embryonic fibroblasts and HeLa cells disrupts ER morphology and loosens ER–mitochondria interactions, thereby reducing the efficiency of mitochondrial Ca2+ uptake in response to stimuli that generate inositol-1,4,5-trisphosphate(PMID:19052620).
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<body>
PACS-2 co-localizes with ADAM17 on early endosomes (PMID:26108729).
PACS-2 controls the apposition of mitochondria with the ER, as depletion of PACS-2 causes BAP31-dependent mitochondria fragmentation and uncoupling from the ER.PACS-2 also controls formation of ER lipid-synthesizing centers found on mitochondria-associated membranes and ER homeostasis.In response to apoptotic inducers, PACS-2 translocates Bid to mitochondria, which initiates a sequence of events including the formation of mitochondrial truncated Bid, the release of cytochrome c, and the activation of caspase-3, thereby causing cell death (PMID:15692567).
The cytosolic sorting protein PACS-2 regulates the distribution and activity of calnexin. Under control conditions, over 80% of calnexin localizes to the ER, mainly at the MAM. However, through a protein-protein interaction, PACS-2 causes calnexin to distribute between the ER and the plasma membrane. PACS-2 thus affects the homeostasis of ER Ca2+ (PMID:19144519.)
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PACS-2 interacts with ADAM17 under basal conditions. It was found that PACS-2 interacted with mature ADAM17, and that PACS-2/ADAM17 co-localization overlapped substantially with transferrin-positive early endosomes. PACS-2 loss did not affect constitutive ADAM17 internalization, but rather decreased the cell-surface recycling and stability of internalized ADAM17. PACS-2 co-localizes with ADAM17 on early endosomes and PACS-2 knockdown decreases the recycling and stability of internalized ADAM17. Hence, PACS-2 sustains ADAM17 cell-surface activity by diverting ADAM17 away from degradative pathways (PMID:26108729).
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