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

Overview

Journal Mol Cell

Publisher Cell Press

Specialty Cell Biology

Date 2015 Mar 10

PMID 25747658

Citations 25

Authors

Brian J McMillan

Bjorn Schnute

Nadja Ohlenhard

Brandon Zimmerman

Laura Miles

Natalia Beglova

Thomas Klein

Stephen C Blacklow

Affiliations

Soon will be listed here.

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.

Citing Articles

Another tail of two sites: activation of the Notch ligand Delta by Mindbomb1.

Vullings N, Airich A, Seib E, Troost T, Klein T BMC Biol. 2025; 23(1):71.

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Engineering synthetic agonists for targeted activation of Notch signaling.

Perez D, Antfolk D, Bustos X, Medina E, Chang S, Ramadan A bioRxiv. 2024; .

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