Journal Article

The same pocket in menin binds both MLL and JUND but has opposite effects on transcription

Gurung, Buddha, Hua, Xianxin, Wan, Ke, Huang, Jing, Merchant, Juanita L., Wan, Bingbing, Lei, Ming, Matkar, Smita, Veniaminova, Natalia A.

2012

Overview

Crystal structures of menin in its free form and in complexes with MLL1 or with JUND, or with an MLL1–LEDGF heterodimer, show that menin contains a deep pocket that binds short peptides of MLL1 or JUND in the same manner, but produces opposite effects on transcription. Menin protein's dual action The nuclear protein menin can both promote tumorigenesis — for instance, it is an oncogenic cofactor in leukaemias induced by MLL translocations — and act as a tumour suppressor, depending on the cell lineage. It interacts with several transcriptional regulators, including the transcription factor JUND and the histone methyltransferase MLL1. Here, the crystal structures of menin in its free form and in complexes with JUND or MLL1 are determined. The structures help to explain menin's opposing effects on transcription. It can block JNK-mediated phosphorylation of JUND and therefore suppress JUND-induced transcription, but it acts as a scaffold to promote formation of a transcriptional complex containing MLL1. Menin is a tumour suppressor protein whose loss or inactivation causes multiple endocrine neoplasia 1 (MEN1), a hereditary autosomal dominant tumour syndrome that is characterized by tumorigenesis in multiple endocrine organs 1 . Menin interacts with many proteins and is involved in a variety of cellular processes 2 , 3 , 4 , 5 , 6 , 7 , 8 . Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity 2 , 9 . Several MEN1 missense mutations disrupt the menin–JUND interaction, suggesting a correlation between the tumour-suppressor function of menin and its suppression of JUND-activated transcription 2 , 10 . Menin also interacts with mixed lineage leukaemia protein 1 (MLL1), a histone H3 lysine 4 methyltransferase, and functions as an oncogenic cofactor to upregulate gene transcription and promote MLL1-fusion-protein-induced leukaemogenesis 5 , 7 , 11 , 12 . A recent report on the tethering of MLL1 to chromatin binding factor lens epithelium-derived growth factor (LEDGF) by menin indicates that menin is a molecular adaptor coordinating the functions of multiple proteins 13 . Despite its importance, how menin interacts with many distinct partners and regulates their functions remains poorly understood. Here we present the crystal structures of human menin in its free form and in complexes with MLL1 or with JUND, or with 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 that it can have opposite effects on transcription. The menin–JUND interaction blocks JUN N-terminal kinase (JNK)-mediated JUND phosphorylation and suppresses JUND-induced transcription. In contrast, menin promotes gene transcription by binding the transcription activator MLL1 through the peptide pocket while still interacting with the chromatin-anchoring protein LEDGF at a distinct surface formed by both menin and MLL1.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 631/337/572 / 631/45/535 / Amino Acid Motifs / Amino Acid Sequence / Animals / Binding Sites / Biological and medical sciences / Chromatin - metabolism / Crystalline structure / Crystallography, X-Ray / Fibroblasts / Fundamental and applied biological sciences. Psychology / Genetic aspects / Genetic transcription / Genetics / HEK293 Cells / Histone-Lysine N-Methyltransferase / Humanities and Social Sciences / Humans / Intercellular Signaling Peptides and Proteins - metabolism / JNK Mitogen-Activated Protein Kinases - metabolism / Kinases / letter / Leukemia / Mice / Models, Molecular / Molecular biophysics / Molecular Sequence Data / multidisciplinary / Mutation / Myeloid-Lymphoid Leukemia Protein - chemistry / Myeloid-Lymphoid Leukemia Protein - metabolism / Phosphorylation / Physiological aspects / Protein Binding / Protein Multimerization / Proteins / Proto-Oncogene Proteins - chemistry / Proto-Oncogene Proteins - metabolism / Proto-Oncogene Proteins c-jun - chemistry / Proto-Oncogene Proteins c-jun - metabolism / Risk factors / Science / Science (multidisciplinary) / Structure in molecular biology / Structure-Activity Relationship / Transcription, Genetic / Tumor proteins