TY - CHAP
T1 - Regulated Alternative Translocation
T2 - A Mechanism Regulating Transmembrane Proteins Through Topological Inversion
AU - Ye, Jin
N1 - Funding Information:
I would like to thank Nancy Heard for graphic illustration. This work was supported by the National Institutes of Health (GM-116106 and HL-20948) and the Welch Foundation (I-1832).
Publisher Copyright:
© 2020, Springer Nature Switzerland AG.
PY - 2021
Y1 - 2021
N2 - 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 dihydroceramide-induced 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 mechanism to regulate transmembrane proteins.
AB - 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 dihydroceramide-induced 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 mechanism to regulate transmembrane proteins.
KW - CCR5
KW - Ceramide
KW - Protein translocation
KW - TM4SF20
KW - Transmembrane proteins
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U2 - 10.1007/5584_2020_585
DO - 10.1007/5584_2020_585
M3 - Chapter
C2 - 32986129
AN - SCOPUS:85102140555
T3 - Advances in Experimental Medicine and Biology
SP - 183
EP - 190
BT - Advances in Experimental Medicine and Biology
PB - Springer
ER -