Intra-Golgi Vesicular Transport and the Secretory Pathway
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.
A Secretory Pathway
B Bimodal Interaction of Coatomer
C Secretory Pathway: p24 Interactions
D Predicted Luminal Interactions
E Wnt Interaction of the p24 Model
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 .