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Title: A Tail of Two Sites: A Bipartite Mechanism for Recognition of Notch Ligands by Mind Bomb E3 Ligases

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. Here we present 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.
 [1] ;  [2] ;  [2] ;  [3] ;  [3] ;  [4] ;  [2] ;  [3]
  1. Harvard Medical School, Boston, MA (United States)
  2. Univ. of Dusseldorf (Germany)
  3. Harvard Medical School, Boston, MA (United States); Dana Farber Cancer Inst., Boston, MA (United States)
  4. Harvard Medical School, Boston, MA (United States); Beth-Israel Deaconess Medical Center, Boston, MA (United States)
Publication Date:
Grant/Contract Number:
AC02-06CH11357; P01 CA119070
Published Article
Journal Name:
Molecular Cell
Additional Journal Information:
Journal Volume: 57; Journal Issue: 5; Journal ID: ISSN 1097-2765
Elsevier - Cell Press
Research Org:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org:
USDOE Office of Science (SC); National Institutes of Health (NIH)
Country of Publication:
United States
OSTI Identifier:
Alternate Identifier(s):
OSTI ID: 1176803; OSTI ID: 1233996