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Updated: May 31, 2026
Production, Crystallization, and Structure Determination of the IKK-binding Domain of NEMO
Published on: December 28, 2019
Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) protein
Marcelo J Murai1, Maksymilian Chruszcz, Gireesh Reddy
1Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
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.
Insights
Menin protein, a tumor suppressor, also drives leukemia by interacting with MLL fusion proteins. Its crystal structure reveals a conserved cavity essential for this MLL binding, offering a new therapeutic target for leukemia.
Area of Science:
- Structural Biology
- Molecular Oncology
- Biochemistry
Background:
- Menin, encoded by the MEN1 gene, functions as a tumor suppressor in endocrine tissues.
- Menin acts as an oncogenic cofactor for mixed lineage leukemia (MLL) fusion proteins in acute leukemias.
- The menin-MLL interaction is crucial for MLL-mediated leukemogenesis and represents a therapeutic target.
Purpose of the Study:
- To determine the crystal structure of a menin homolog from Nematostella vectensis.
- To elucidate the structural basis of the menin-MLL interaction.
- To provide insights for developing novel anti-leukemia agents targeting the menin-MLL interaction.
Main Methods:
- X-ray crystallography to determine the 3D structure of Nematostella vectensis menin.
- Sequence comparison to infer structural similarity between Nematostella and human menin.
- Site-directed mutagenesis to identify the MLL binding site within the menin structure.
Main Results:
- The crystal structure of Nematostella menin revealed a predominantly α-helical protein with a conserved central cavity.
- This central cavity was identified as the binding site for MLL through site-directed mutagenesis.
- High sequence similarity suggests conserved structure and function between Nematostella and human menin.
Conclusions:
- The study provides the first crystal structure of a menin homolog, revealing a conserved MLL binding cavity.
- This structural information offers a basis for understanding menin's dual role as a tumor suppressor and oncogenic cofactor.
- The findings are critical for designing targeted inhibitors against the menin-MLL interaction for leukemia therapy.
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