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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  p24/TMED 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

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G  Collagen Binding in Docking

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H  Collagen Binding of TMED10

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I  Binding to X-Ray Structures?

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J  Bacterial Protein Collagen Binding

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K  Considering a Random Chain

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L  Considering the Young's Modulus

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 and collagen as analyzed with molecular docking (E, F). Collagen interaction in docking is shown for modeled TMED2 and the solved TMED10 structure (G, H). Comparison of solved TMED2 and TMED10 structures with the PDB database and the structural overlay of TMED10 and the collagenase-domain of bacterial source including the molecular docking, validated the overall model-docking test (I, J). Surprisingly, in Drosophila it was found that logjam (p24/TMED2) was involved in collagen secretion in a genetic screen . In addition, 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 . With respect to collagen binding and vesicular transport a model is put forward that would assume that collagen flexibility before further assembly, allows incorporation into small carrier vesicles and not only megacarriers (K, L)(see also Talks). In view of transported cargo and the homo- and heterooligomeric nature of TMED proteins, it is tempting to speculate about a multitude and/or of bidentate interactions.

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References
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Update 2019
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