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Intra-Golgi Vesicular Transport and the Secretory Pathway

Klaus Fiedler

In a line of research at the Memorial Sloan-Kettering Cancer Center (Prof. James Rothman`s laboratory) intra-Golgi transport (A) was analyzed in a model setting and the cytoplasmic domain of the putative cargo receptor p24-TMED2 was shown to interact with coatomer (the Golgi coat) suggestive of bimodal interaction of coatomer with different signals and bimodal sorting (B) . Today, numerous new elegant studies are suggestive of the tri- or multi-modal sorting capacity of coatomer and the structural analysis had proven the original assignment to coatomer subcomplexes that I had found. The transmembrane domain of TMED proteins contains an extended motif involving a glutamine residue close to the cytoplasmic domain which interacts with sphingomyelin 18 and permits transport of p24 from the endoplasmic reticulum (ER) and Golgi to later stations in the secretory route (see also Supplementary Data). Moreover, the p24 protein that I had analyzed (C), showed a distinct pattern of several signals within the transmembrane/cytoplasmic domains establishing the role of signals in forward and backward trafficking.
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A  Secretory Pathway

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B  Bimodal Interaction of Coatomer

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C  Secretory Pathway: p24 Interactions

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D  Predicted Luminal Interactions

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E  Wnt Interaction of the p24 Model

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F  Carbohydrate Binding of the Model

Vesicular traffic and cargo sorting is thus intricately regulated and p24 has e.g. been recently shown to have proviral activity in dengue virus infection , and recently p23-TMED10 , another member of the TMED-family, was implicated in vaccinia virus infection . Lately, this sphingomyelin-binding motif, originally found in the p24-TMED2 and gamma secretase, has been described in several other polypeptides such as tetraspanin-7 . p23-TMED10 was previously found to interact with the presenilin complex, important in signaling in the Notch pathway and Alzheimer APP processing (D) . p24-TMED2 may interact with Wnt proteins similar to the recently discovered and confirmed interaction of mammalian Wnt3-Fz8, and, moreover, p23-TMED10 and p24-TMED2 may both interact with N-glycans as analyzed with molecular docking (see figshare) (E, F). Surprisingly, in a recent study with a shTMED9 knockout in primary human colon cancer cells, it is found that among several coregulated expressed proteins, the Wnt11 protein and regulators of the Wnt-pathway are up- whereas, for example, the Anxa13 (see also the page on epithelia and polarity) and Col9a3 are significantly downregulated .

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References
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Fiedler, K. The Wnt segment polarity pathway and TMED2 protein may interact via a lectin- and decoy-type mechanism. bioRxiv. 2016; 056531 (doi: http://dx.doi.org/10.1101/056531).
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Update 2019
KEYWORDS for SlideShow caveolae caveolin VIP36 VIP21 flotillin Pfad Analyse pathway analysis analysed cavatellin reggie MVP17 VIP17 cytochrome b5 XIII V II mechanosignaling mechanosignalling mechanotransduction Mechanotransduktion tensegrity leguminous Bauhinia lectin Lektin plant-like CRD calcium-binding p24 TMED protein COP alpha beta gamma zeta epsilon coatomer conformer conformation stack cisternae secretory transport vesicle vesicular Vesikel secretion Sekretion brain cell Zelle fMRI voxel based morphometry VBM hypertensive crisis clinical decision modeling modelling modelling crises scaling Hypertensive Krisen blood pressure silica beads perfusion coating lung immuno-isolation Immunoisolation purification Blutdruck Bluthochdruck hypertension multivariate statistics regression neural network ranks dimensionality machine reduction endocytosis Endozytose transcytosis adsorptive Transzytose paracellular parazellulär transcellular transzellulär epithelia Epithelien apical basal basolateral lateral polarity Polarität ESEM environmental scanning endothelia endothelium Endothelien vasculature Gefässe blood pressure vessel lumen luminal MDCK COS SVEC 4-10 Eahy 926 ECV304 BAEC CPAE mass spectrometry gel electrophoresis SDS-PAGE 2-D affinity chromatography two-dimensional proteomics time of flight micro-sequencing confocal plasma membrane surface DIC detergent complex trans-Golgi apparatus plasmalemmal Apparat complex Komplex ER endoplasmatisches Retikulum endoplasmic reticulum Reduktase NAD(P)H desaturase nucleus Nukleus lipid sterol cholesterol glycosphingolipid Sphingolipide spingomyelin GM1 Gangliosid Ceramid ceramide Transporter Ionen-Kanal ion channel membrane curvature tension viscosity flow LDL temperature low-density lipoprotein high-density merocrine Merokrin paracrine signaling