Regulated Alternative Translocation: A Mechanism Regulating Transmembrane Proteins Through Topological Inversion
Transmembrane proteins must adopt a proper topology to execute their functions. In mammalian cells, a transmembrane protein is believed to adopt a fixed topology. This assumption has been challenged by recent reports that ceramide or related sphingolipids
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Regulated Alternative Translocation: A Mechanism Regulating Transmembrane Proteins Through Topological Inversion Jin Ye Abstract
Transmembrane proteins must adopt a proper topology to execute their functions. In mammalian cells, a transmembrane protein is believed to adopt a fixed topology. This assumption has been challenged by recent reports that ceramide or related sphingolipids regulate some transmembrane proteins by inverting their topology. Ceramide inverts the topology of certain newly synthesized polytopic transmembrane proteins by altering the direction through which their first transmembrane helices are translocated across membranes. Thus, this regulatory mechanism has been designated as Regulated Alternative Translocation (RAT). The physiological importance of this topological regulation has been demonstrated by the finding that ceramide-induced RAT of TM4SF20 (Transmembrane 4 L6 family member 20) is crucial for the effectiveness of doxorubicin-based chemotherapy, and that dihydroceramideinduced RAT of CCR5 (C-C chemokine receptor type 5), a G protein-coupled receptor, is required for lipopolysaccharide (LPS) to inhibit chemotaxis of macrophages. These observations suggest that topological inversion through RAT could be an emerging J. Ye (*) Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX, USA e-mail: [email protected]
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Keywords
CCR5 · Ceramide · Protein translocation · TM4SF20 · Transmembrane proteins
Abbreviations CCR5 CREB3L1 ER GPCR LPS RAT RIP TM4SF20 TRAM
1
C-C chemokine receptor 5 cAMP responsive element binding protein 3-like 1 endoplasmic reticulum G protein-coupled receptor lipopolysaccharide regulated alternative translocation regulated intramembrane proteolysis Transmembrane 4 L6 family member 20 Translocating chain-associated membrane protein
Introduction
Cellular membranes are physical barriers that are impermeable to many molecules. Thus, unlike cytosolic and nuclear proteins that are surrounded by homogenous environment, transmembrane proteins are all polarized, as segments of
J. Ye
transmembrane proteins localized at different sides of membranes are exposed to distinct environment. As a result, the topology of transmembrane proteins, which depicts their orientation across membranes, is critical for their functions. The topology of transmembrane proteins is primarily determined during their synthesis on endoplasmic reticulum (ER) membranes (Zimmermann et al. 2011). For transmembrane proteins that contain a single transmembrane helix, the translocation process has been categorized into three classes (Fig. 1) (Lodish et al. 2007). Type I insertion refers to proteins that contain a cleavable ER-targeting signal peptide N-terminal to the first transmembrane helix. The signal recognition particle binds to the hydrophobic sequence within a nascent signal peptide, directing the ribosome/nascent polypeptide complex to the ER membranes. The signal peptide is then inserted into membranes ad
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