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Mol Cell. 2015 Mar 5;57(5):912-924. doi: 10.1016/j.molcel.2015.01.019.

A tail of two sites: a bipartite mechanism for recognition of notch ligands by mind bomb E3 ligases.

Author information

1
Harvard Medical School, Boston, MA 02115, USA.
2
University of Dusseldorf, Dusseldorf 40225, Germany.
3
Harvard Medical School, Boston, MA 02115, USA; Dana Farber Cancer Institute, Boston, MA 02215 USA.
4
Harvard Medical School, Boston, MA 02115, USA; Beth-Israel Deaconess Medical Center, Boston, MA, 02215 USA.
5
Harvard Medical School, Boston, MA 02115, USA; Dana Farber Cancer Institute, Boston, MA 02215 USA. Electronic address: Stephen_Blacklow@hms.harvard.edu.

Erratum in

  • Mol Cell. 2015 Apr 16;58(2):387.

Abstract

Mind bomb (Mib) proteins are large, multi-domain E3 ligases that promote ubiquitination of the cytoplasmic tails of Notch ligands. This ubiquitination step marks the ligand proteins for epsin-dependent endocytosis, which is critical for in vivo Notch receptor activation. We present here crystal structures of the substrate recognition domains of Mib1, both in isolation and in complex with peptides derived from Notch ligands. The structures, in combination with biochemical, cellular, and in vivo assays, show that Mib1 contains two independent substrate recognition domains that engage two distinct epitopes from the cytoplasmic tail of the ligand Jagged1, one in the intracellular membrane proximal region and the other near the C terminus. Together, these studies provide insights into the mechanism of ubiquitin transfer by Mind bomb E3 ligases, illuminate a key event in ligand-induced activation of Notch receptors, and identify a potential target for therapeutic modulation of Notch signal transduction in disease.

PMID:
25747658
PMCID:
PMC4355479
DOI:
10.1016/j.molcel.2015.01.019
[Indexed for MEDLINE]
Free PMC Article

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