Regulated Alternative Translocation: A Mechanism Regulating Transmembrane Proteins Through Topological Inversion

Research output: Chapter in Book/Report/Conference proceedingChapter

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 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.

Original languageEnglish (US)
Title of host publicationAdvances in Experimental Medicine and Biology
PublisherSpringer
Pages183-190
Number of pages8
DOIs
StatePublished - 2021

Publication series

NameAdvances in Experimental Medicine and Biology
Volume21
ISSN (Print)0065-2598
ISSN (Electronic)2214-8019

Keywords

  • CCR5
  • Ceramide
  • Protein translocation
  • TM4SF20
  • Transmembrane proteins

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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