The intracellular region of the Notch ligand Jagged-1 gains partial structure upon binding to synthetic membranes

Matija Popovic, Alfredo De Biasio, Alessandro Pintar, Sándor Pongor

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

Abstract

Notch ligands are membrane-spanning proteins made of a large extracellular region, a transmembrane segment, and a ∼ 100-200 residue cytoplasmic tail. The intracellular region of Jagged-1, one of the five ligands to Notch receptors in man, mediates protein-protein interactions through the C-terminal PDZ binding motif, is involved in receptor/ligand endocytosis triggered by mono-ubiquitination, and, as a consequence of regulated intramembrane proteolysis, can be released into the cytosol as a signaling fragment. The intracellular region of Jagged-1 may then exist in at least two forms: as a membrane-tethered protein located at the interface between the membrane and the cytoplasm, and as a soluble nucleocytoplasmic protein. Here, we report the characterization, in different environments, of a recombinant protein corresponding to the human Jagged-1 intracellular region (J1_tmic). In solution, J1_tmic behaves as an intrinsically disordered protein, but displays a significant helical propensity. In the presence of SDS micelles and phospholipid vesicles, used to mimick the interface between the plasma membrane and the cytosol, J1_tmic undergoes a substantial conformational change. We show that the interaction of J1_tmic with SDS micelles drives partial helix formation, as measured by circular dichroism, and that the helical content depends on pH in a reversible manner. An increase in the helical content is observed also in the presence of vesicles made of negatively charged, but not zwitterionic, phospholipids. We propose that this partial folding may have implications in the interactions of J1_tmic with its binding partners, as well as in its post-translational modifications. © 2007 The Authors.
Original languageEnglish (US)
Pages (from-to)5325-5336
Number of pages12
JournalFEBS Journal
Volume274
Issue number20
DOIs
StatePublished - Oct 1 2007
Externally publishedYes

ASJC Scopus subject areas

  • Biochemistry
  • Cell Biology
  • Molecular Biology

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