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Title: Crystal Structure of Menin Reveals Binding Site for Mixed Lineage Leukemia (MLL) Protein

Menin is a tumor suppressor protein that is encoded by the MEN1 (multiple endocrine neoplasia 1) gene and controls cell growth in endocrine tissues. Importantly, menin also serves as a critical oncogenic cofactor of MLL (mixed lineage leukemia) fusion proteins in acute leukemias. Direct association of menin with MLL fusion proteins is required for MLL fusion protein-mediated leukemogenesis in vivo, and this interaction has been validated as a new potential therapeutic target for development of novel anti-leukemia agents. Here, we report the first crystal structure of menin homolog from Nematostella vectensis. Due to a very high sequence similarity, the Nematostella menin is a close homolog of human menin, and these two proteins likely have very similar structures. Menin is predominantly an {alpha}-helical protein with the protein core comprising three tetratricopeptide motifs that are flanked by two {alpha}-helical bundles and covered by a {beta}-sheet motif. A very interesting feature of menin structure is the presence of a large central cavity that is highly conserved between Nematostella and human menin. By employing site-directed mutagenesis, we have demonstrated that this cavity constitutes the binding site for MLL. Our data provide a structural basis for understanding the role of menin as a tumor suppressormore » protein and as an oncogenic co-factor of MLL fusion proteins. It also provides essential structural information for development of inhibitors targeting the menin-MLL interaction as a novel therapeutic strategy in MLL-related leukemias.« less
Authors:
; ; ; ;  [1] ;  [2]
  1. (Michigan)
  2. (
Publication Date:
OSTI Identifier:
1027133
Resource Type:
Journal Article
Resource Relation:
Journal Name: J. Biol. Chem.; Journal Volume: 286; Journal Issue: (36) ; 09, 2011
Research Org:
Advanced Photon Source (APS), Argonne National Laboratory (ANL), Argonne, IL (US)
Sponsoring Org:
OTHER
Country of Publication:
United States
Language:
ENGLISH
Subject:
59 BASIC BIOLOGICAL SCIENCES; 60 APPLIED LIFE SCIENCES; CRYSTAL STRUCTURE; CRYSTALLOGRAPHY; GENES; IN VIVO; LEUKEMIA; LEUKEMOGENESIS; MUTAGENESIS; NEOPLASMS; PROTEIN STRUCTURE; PROTEINS; TARGETS