5AIZ

The PIAS-like coactivator Zmiz1 is a direct and selective cofactor of Notch1 in T-cell development and leukemia

Summary for 5AIZ

• Entry DOI: 10.2210/pdb5aiz/pdb
• Descriptor: ZINC FINGER MIZ DOMAIN-CONTAINING PROTEIN 1, UNKNOWN ATOM OR ION, 1,2-ETHANEDIOL, ... (5 entities in total)
• Functional Keywords: zinc-binding protein, protein
• Biological source: HOMO SAPIENS (HUMAN)
• Cellular location: Nucleus speckle : Q9ULJ6
• Total number of polymer chains: 1
• Total formula weight: 14348.70

Authors

Cho, H.J.,Murai, M.,Chiang, M.,Cierpicki, T. (deposition date: 2015-02-18, release date: 2015-10-28, Last modification date: 2024-11-13)

Primary citation

Cho, H.J.,Chiang, M.,Cierpicki, T.
The Pias-Like Coactivator Zmiz1 is a Direct and Selective Cofactor of Notch1 in T-Cell Development and Leukemia
Immunity, 43:870-, 2015

PubMed Abstract: Pan-NOTCH inhibitors are poorly tolerated in clinical trials because NOTCH signals are crucial for intestinal homeostasis. These inhibitors might also promote cancer because NOTCH can act as a tumor suppressor. We previously reported that the PIAS-like coactivator ZMIZ1 is frequently co-expressed with activated NOTCH1 in T cell acute lymphoblastic leukemia (T-ALL). Here, we show that similar to Notch1, Zmiz1 was important for T cell development and controlled the expression of certain Notch target genes, such as Myc. However, unlike Notch, Zmiz1 had no major role in intestinal homeostasis or myeloid suppression. Deletion of Zmiz1 impaired the initiation and maintenance of Notch-induced T-ALL. Zmiz1 directly interacted with Notch1 via a tetratricopeptide repeat domain at a special class of Notch-regulatory sites. In contrast to the Notch cofactor Maml, which is nonselective, Zmiz1 was selective. Thus, targeting the NOTCH1-ZMIZ1 interaction might combat leukemic growth while avoiding the intolerable toxicities of NOTCH inhibitors.

PubMed: 26522984
DOI: 10.1016/J.IMMUNI.2015.10.007

Experimental method

X-RAY DIFFRACTION (1.7 Å)