Structural highlights
Publication Abstract from PubMedMenin 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 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. Crystal Structure of Menin Reveals Binding Site for Mixed Lineage Leukemia (MLL) Protein.,Murai MJ, Chruszcz M, Reddy G, Grembecka J, Cierpicki T J Biol Chem. 2011 Sep 9;286(36):31742-8. Epub 2011 Jul 13. PMID:21757704[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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