Intralumenal docking of Cx36 channels in the ER isolates mis-trafficked protein
Tetenborg, S.; Liss, V.; Breitsprecher, L.; Timonina, K.; Kotova, A.; Hecker, A. J. A.; Yuan, C.; Shihabeddin, E.; Dedek, K.; Zoidl, G.; Hensel, M.; O`Brien, J.
Show abstract
The intracellular domains of connexins are essential for the assembly of gap junctions. For connexin 36 (Cx36), the major neuronal connexin, it has been shown that a dysfunctional PDZ binding motif interferes with electrical synapse formation. However, it is still unknown how this motif coordinates the transport of Cx36. In the present study, we characterize a phenotype of Cx36 mutants that lack a functional PDZ binding motif using HEK293T cells as an expression system. We provide evidence that an intact PDZ binding motif is critical for proper ER export of Cx36. Removing the PDZ binding motif of Cx36 results in ER retention and the formation of multi-membrane vesicles containing gap junction-like connexin aggregates. Using a combination of site directed mutagenesis and electron micrographs we reveal that these vesicles consist of Cx36 channels that docked prematurely in the ER. Our data suggest a model in which ER-retained Cx36 channels reshape the ER membrane into concentric whorls that are released into the cytoplasm.
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