Menin is a tumor suppressor protein whose loss or inactivation causes multiple endocrine neoplasia type 1 (MEN1), a hereditary autosomal dominant tumor syndrome characterized by tumorigenesis in multiple endocrine organs1. Menin interacts with a multitude of proteins and involves in a variety of cellular processes2–6. Menin binds the Jun family transcription factor JunD and inhibits its transcriptional activity7,8. Several MEN1 missense mutations disrupted the menin-JunD interaction suggestive of a correlation between menin’s tumor suppressor function and its interaction with JunD and suppression of JunD activated transcription8,9. Menin also interacts with mixed lineage leukemia protein 1 MLL1, a histone H3 lysine 4 (H3K4) methyltransferase, and functions as an oncogenic cofactor to upregulate gene (including HOX genes) transcription and promote MLL1 fusion protein (MFP)-induced leukemogenesis10–12. A recent report on menin tethering MLL1 to chromatin binding factor LEDGF indicates menin as a molecular adaptor to coordinate the functions of multiple proteins13. Despite the importance of menin, it still remains poorly understood how menin could interact with many distinct partners and control multiple functions. Here we present the crystal structures of menin, free and in complexes with MLL1 or JunD, or an MLL1-LEDGF heterodimer. These structures show that menin contains a deep pocket that binds short peptides of MLL1 or JunD in the same manner, but oppositely regulates transcription. The menin-JunD interaction blocks JNK kinase-meidated JunD phosphorylation, a crucial event for JunD activation.Moreover, menin functions as a scaffold molecule to promote gene transcription by binding MLL1 through the peptide-pocket yet interacting with LEDGF at a distinct surface.
The protein menin is encoded by the MEN1 gene, which is mutated in patients with multiple endocrine neoplasia type 1 (MEN1) syndrome. Although menin acts as a tumor suppressor in endocrine organs, it is required for leukemic transformation in mouse models. Menin possesses these dichotomous functions likely because it can both positively and negatively regulate gene expression as well as interact with a multitude of proteins with diverse functions. Here we review the recent progress in understanding the molecular mechanisms by which menin functions. The crystal structures of menin with different binding partners reveal that menin is a key scaffold protein that functionally crosstalks with various partners to regulate gene transcription and interplay with multiple signaling pathways.
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