LIG_Menin_MBM1_1

Menin is an ubiquitously expressed nuclear protein conserved in vertebrates and also studied in Drosophila. It is involved in a complex network of interactions with diverse proteins such as transcription activators, transcription repressors, and other cell signaling proteins. Due to these numerous interacting partners, Menin is involved in different biological pathways such as cell growth regulation, cell cycle control, genome stability, bone development, and hematopoiesis. Menin is dichotomous in function as it acts as a tumour suppressor in endocrine glands and an oncogenic cofactor of MLL fusion proteins (Matkar,2013). Mutations in Menin cause multiple endocrine neoplasia type 1 (MEN1) syndrome that is characterized by the formation of tumours in endocrine organs including the pituitary gland, the parathyroid gland, and pancreatic islets. Menin interacts with different proteins depending on the cellular lineage. One important Menin-mediated interaction is through Menin binding motifs (MBMs). They are short stretches of conserved residues present in the N-terminus of some Menin-binding proteins such as MLL1,2 and JunD (Murai,2011). Drosophila trx is the functional homologue of the mammalian MLL1 gene (Shilatifard,2012). It also contains an MBM motif but the interaction with fly menin is not experimentally identified. Note that the human paralogues MLL3/KMT2C and MLL4/KMT2D lack the MBM, do not form complexes with menin and have somewhat different functional roles (Crump,2019).
The structure of Menin is like a curved left hand, in which the N-terminal domain is depicted as a thumb, the middle region adopts the shape of the palm, and the C-terminus resembles curved fingers. The deep central pocket in the palm region is responsible for MBM binding. This cavity is formed by several α helices from the three tetratricopeptide repeat (TRP) motifs and the N- and C-terminal helical bundle domains. The MBM-binding interface is characterized by a number of hydrophobic residues as well as several acidic side chains that create a strong negative surface potential (Huang,2012). MBM peptides are deeply plugged into the cavity comprising two short fragments MBM1 and MBM2. They are separated by a 7 residue (mainly) polyglycine linker which remains flexible in the complex and dispensable for the interaction. MBM1 is a high-affinity binding motif that binds Menin in an extended conformation with an affinity 20 times higher compared with MBM2. The MBM2 peptide is positively charged and binds in a region proximal to the MBM1 binding site and provides additional stability to the interaction of MLL with Menin. MBM1 is the key target site for the inhibition of the MLL-Menin complex (Grembecka,2010).
Menin can both positively and negatively regulate gene transcription. The complexes with the histone methyl transferases MLL1 and MLL2 methylate histone H3K4, enabling more open chromatin conformation for gene transcription. As in the case of Acute leukaemia, Menin is frequently associated with MBM1s of both MLL-wild type and MLL-fusion proteins and upregulates the expression levels of downstream target genes such as HOX, resulting in malignant cell proliferation. Two small molecule inhibitors KO-539, and SNDX-5613 targeting this interaction have been in clinical trials (Lei,2021). Of all the AP-1 family members, Menin interacts only with JunD and represses JunD-mediated transcriptional activation that negatively regulates the expression of the gastrin gene in human AGS gastric cells. Moreover, it also acts as a scaffold protein by assembling the Menin–MLL1–LEDGF complex that also positively regulates MLL1-induced leukaemogenesis (Murai,2014).