title: Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein.
abstract: 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 α-helical protein with the protein core comprising three tetratricopeptide motifs that are flanked by two α-helical bundles and covered by a β-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 suppressor 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.
authors.affiliation: Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Murai
authors.forename: Maksymilian
authors.initials: M
authors.lastname: Chruszcz
authors.forename: Gireesh
authors.initials: G
authors.lastname: Reddy
authors.forename: Jolanta
authors.initials: J
authors.lastname: Grembecka
authors.forename: Tomasz
authors.initials: T
authors.lastname: Cierpicki
mesh_terms: D000818:Animals; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006801:Humans; D016297:Mutagenesis, Site-Directed; D051788:Myeloid-Lymphoid Leukemia Protein / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D017433:Protein Structure, Secondary; D011518:Proto-Oncogene Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012615:Sea Anemones; D017386:Sequence Homology, Amino Acid; D025521:Tumor Suppressor Proteins
chemical_list: C105373:MEN1 protein, human; D011518:Proto-Oncogene Proteins; D025521:Tumor Suppressor Proteins; D051788:Myeloid-Lymphoid Leukemia Protein