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Stefanovic, B, Stefanovic, L, Schnabl, B, Bataller, R and Brenner, DA (2004) TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis. Mol. Cell. Biol. 24:1758-68
Cotranslational insertion of type I collagen chains into the lumen of the endoplasmic reticulum (ER) and their subsequent folding into a heterotrimeric helix is a complex process which requires coordinated action of the translation machinery, components of translocons, molecular chaperones, and modifying enzymes. Here we describe a role for the protein TRAM2 in collagen type I expression in hepatic stellate cells (HSCs) and fibroblasts. Activated HSCs are collagen-producing cells in the fibrotic liver. Quiescent HSCs produce trace amounts of type I collagen, while upon activation collagen synthesis increases 50- to 70-fold. Likewise, expression of TRAM2 dramatically increases in activated HSCs. TRAM2 shares 53% amino acid identity with the protein TRAM, which is a component of the translocon. However, TRAM2 has a C terminus with only a 15% identity. The C-terminal part of TRAM2 interacts with the Ca(2+) pump of the ER, SERCA2b, as demonstrated in a Saccharomyces cerevisiae two-hybrid screen and by immunoprecipitations in human cells. TRAM2 also coprecipitates with anticollagen antibody, suggesting that these two proteins interact. Deletion of the C-terminal part of TRAM2 inhibits type I collagen synthesis during activation of HSCs. The pharmacological inhibitor of SERCA2b, thapsigargin, has a similar effect. Depletion of ER Ca(2+) with thapsigargin results in inhibition of triple helical collagen folding and increased intracellular degradation. We propose that TRAM2, as a part of the translocon, is required for the biosynthesis of type I collagen by coupling the activity of SERCA2b with the activity of the translocon. This coupling may increase the local Ca(2+) concentration at the site of collagen synthesis, and a high Ca(2+) concentration may be necessary for the function of molecular chaperones involved in collagen folding.
Amino Acid Sequence; Animals; Calcium/metabolism; Calcium-Transporting ATPases/antagonists & inhibitors; Calcium-Transporting ATPases/metabolism; Cells, Cultured; Cloning, Molecular; Collagen Type I/biosynthesis; Collagen Type I/chemistry; Collagen Type I/genetics; Collagen Type I/metabolism; Disulfides/metabolism; Endoplasmic Reticulum/drug effects; Endoplasmic Reticulum/enzymology; Endoplasmic Reticulum/metabolism; Fibroblasts/drug effects; Fibroblasts/metabolism; Hepatocytes/metabolism; Humans; Imidazoles/pharmacology; Membrane Glycoproteins/chemistry; Membrane Glycoproteins/genetics; Membrane Glycoproteins/metabolism; Mice; Molecular Sequence Data; Protein Binding; RNA, Messenger/genetics; RNA, Messenger/metabolism; Rats; Sarcoplasmic Reticulum Calcium-Transporting ATPases; Sequence Deletion; Thapsigargin/pharmacology