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

Nature volume 482, pages 542–546 (2012)Cite this article

Subjects

Abstract

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 organs1. Menin interacts with many proteins and is involved in a variety of cellular processes2,3,4,5,6,7,8. Menin binds the JUN family transcription factor JUND and inhibits its transcriptional activity2,9. 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 transcription2,10. 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 leukaemogenesis5,7,11,12. 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 proteins13. 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.

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Figure 1: Overview of the human menin–MLL1 MBM complex structure.
Figure 2: Structural and mutational analyses of the menin–MLL1 MBM interaction.
Figure 3: Structure of the menin–MLL1 MBM-LBM –LEDGF IBD ternary complex.
Figure 4: Structural and functional studies of the menin–JUND interaction.

Accession codes

Primary accessions

Protein Data Bank

Data deposits

The atomic coordinates and structure factors of menin, menin– MLL1MBM, menin–JUNDMBM, and menin–MLL1MBM-LBM–LEDGFIBD have been deposited in the RCSB Protein Data Bank under accession codes 3U84, 3U85, 3U86 and 3U88, respectively.

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Acknowledgements

We thank G. Wilding for the human JUND complementary DNA and P. Cherepanov for the human LEDGF cDNA. We thank Y. Chen and W. Deng for help at various stages of the project. M.L. is a Howard Hughes Medical Institute Early Career Scientist. Work was supported by National Institutes of Health grants (GM 083015-01 to M.L., R01-DK085121 to X.H. and R37-DK45729 to J.L.M.), an American Cancer Society Research Scholar grant (to M.L.) and an American Association for Cancer Research Caring for Carcinoid Foundation Grant (to X.H.). The General Medicine and Cancer Institutes Collaborative Access Team has been funded in whole or in part with federal funds from the National Cancer Institute (grant Y1-CO-1020) and the National Institute of General Medical Science (grant Y1-GM-1104). Use of the Advanced Photon Source was supported by the US Department of Energy, Office of Science, Office of Basic Energy Sciences, under contract number DE-AC02-06CH11357.

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Author notes

  1. Buddha Gurung and Bingbing Wan: These authors contributed equally to this work.

Authors and Affiliations

  1. Howard Hughes Medical Institute, University of Michigan Medical School, 1150 West. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Jing Huang, Bingbing Wan, Ke Wan & Ming Lei

  2. Department of Biological Chemistry, University of Michigan Medical School, 1150 West. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Jing Huang, Bingbing Wan, Ke Wan & Ming Lei

  3. Department of Cancer Biology, Abramson Family Cancer Research Institute, University of Pennsylvania Perelman School of Medicine, Philadelphia, 19104, Pennsylvania, USA

    Buddha Gurung, Smita Matkar & Xianxin Hua

  4. Department of Internal Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109, USA,

    Natalia A. Veniaminova & Juanita L. Merchant

  5. Department of Molecular and Integrative Physiology, Division of Gastroenterology, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, Michigan 48109, USA,

    Juanita L. Merchant

Authors
  1. Jing Huang
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Contributions

J.H. is responsible for the bulk of the experiments, B.G. for the qRT-PCR and ChIP assays; B.W. for the co-immunoprecipitation and in vivo phosphorylation analyses, S.M. for the luciferase assay, N.A.V. and J.L.M. for the analysis of gastrin expression, and K.W. for some of the protein purification. M.L. and X.H. supervised the project and wrote the paper.

Corresponding authors

Correspondence to Xianxin Hua or Ming Lei.

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The authors declare no competing financial interests.

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Supplementary Information

This file contains Supplementary Figures 1-19 with legends, Supplementary Tables 1-6, Supplementary Text, a Supplementary Discussions and additional references. (PDF 2464 kb)

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Huang, J., Gurung, B., Wan, B. et al. The same pocket in menin binds both MLL and JUND but has opposite effects on transcription. Nature 482, 542–546 (2012). https://doi.org/10.1038/nature10806

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