title: Inverting the Topology of a Transmembrane Protein by Regulating the Translocation of the First Transmembrane Helix.
abstract: TM4SF20 (transmembrane 4 L6 family 20) is a polytopic membrane protein that inhibits proteolytic processing of CREB3L1 (cAMP response element-binding protein 3-like 1), a membrane-bound transcription factor that blocks cell division and activates collagen synthesis. Here we report that ceramide stimulates CREB3L1 cleavage by inverting the orientation of TM4SF20 in membranes. In the absence of ceramide, the N terminus of the first transmembrane helix of TM4SF20 is inserted into the endoplasmic reticulum (ER) lumen. This translocation requires TRAM2 (translocating chain-associated membrane protein 2), a membrane protein containing a putative ceramide-interacting domain. In the presence of ceramide, the N terminus of the first transmembrane domain of TM4SF20 is exposed to cytosol. Consequently, the membrane topology of TM4SF20 is inverted, and this form of TM4SF20 stimulates CREB3L1 cleavage. In the presence of ceramide, translocation of TM4SF20 is TRAM2-independent. We designate this mechanism-causing regulated inversion of the membrane topology as "regulated alternative translocation."
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: Qiuyue
authors: Q
authors: Chen
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: Bray
authors: B
authors: Denard
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: Ching-En
authors: CE
authors: Lee
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: Sungwon
authors: S
authors: Han
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA.
authors: James S
authors: JS
authors: Ye
authors: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390-9046, USA. Electronic address: jin.ye@utsouthwestern.edu.
authors: Jin
authors: J
authors: Ye
mesh_terms: D000072283:A549 Cells; D001665:Binding Sites; D002518:Ceramides / Q000378:metabolism*; D017362:Cyclic AMP Response Element-Binding Protein / Q000737:chemistry / Q000378:metabolism*; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D009154:Mutation; D009419:Nerve Tissue Proteins / Q000737:chemistry / Q000378:metabolism*; D011485:Protein Binding; D000072756:Protein Conformation, alpha-Helical; D021381:Protein Transport; D059748:Proteolysis; D034622:RNA Interference; D012697:Serine Endopeptidases / Q000378:metabolism; D013329:Structure-Activity Relationship; D059470:Tetraspanins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014162:Transfection
chemical_list: C485618:CREB3L1 protein, human; D002518:Ceramides; D017362:Cyclic AMP Response Element-Binding Protein; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; C585005:TM4SF20 protein, human; C486173:TRAM2 protein, human; D059470:Tetraspanins; C101954:N-caproylsphingosine; D012697:Serine Endopeptidases; C026515:type I signal peptidase