PMID- 22327296
OWN - NLM
STAT- MEDLINE
DCOM- 20120329
LR  - 20211021
IS  - 1476-4687 (Electronic)
IS  - 0028-0836 (Print)
IS  - 0028-0836 (Linking)
VI  - 482
IP  - 7386
DP  - 2012 Feb 12
TI  - The same pocket in menin binds both MLL and JUND but has opposite effects on 
      transcription.
PG  - 542-6
LID - 10.1038/nature10806 [doi]
AB  - 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. Menin 
      interacts with many proteins and is involved in a variety of cellular processes. 
      Menin binds the JUN family transcription factor JUND and inhibits its 
      transcriptional activity. 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. 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. 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. 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.
FAU - Huang, Jing
AU  - Huang J
AD  - Howard Hughes Medical Institute, University of Michigan Medical School, Ann 
      Arbor, Michigan 48109, USA.
FAU - Gurung, Buddha
AU  - Gurung B
FAU - Wan, Bingbing
AU  - Wan B
FAU - Matkar, Smita
AU  - Matkar S
FAU - Veniaminova, Natalia A
AU  - Veniaminova NA
FAU - Wan, Ke
AU  - Wan K
FAU - Merchant, Juanita L
AU  - Merchant JL
FAU - Hua, Xianxin
AU  - Hua X
FAU - Lei, Ming
AU  - Lei M
LA  - eng
SI  - PDB/3U84
SI  - PDB/3U85
SI  - PDB/3U86
SI  - PDB/3U88
GR  - Y1-GM-1104/GM/NIGMS NIH HHS/United States
GR  - R01-DK085121/DK/NIDDK NIH HHS/United States
GR  - HHMI/Howard Hughes Medical Institute/United States
GR  - R37-DK45729/DK/NIDDK NIH HHS/United States
GR  - GM083015-01/GM/NIGMS NIH HHS/United States
GR  - R01 GM083015/GM/NIGMS NIH HHS/United States
GR  - R01 DK097555/DK/NIDDK NIH HHS/United States
GR  - R01 DK085121/DK/NIDDK NIH HHS/United States
GR  - Y1-CO-1020/CO/NCI NIH HHS/United States
GR  - R37 DK045729/DK/NIDDK NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20120212
PL  - England
TA  - Nature
JT  - Nature
JID - 0410462
RN  - 0 (Chromatin)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (JunD protein, human)
RN  - 0 (KMT2A protein, human)
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Proto-Oncogene Proteins c-jun)
RN  - 0 (lens epithelium-derived growth factor)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
RN  - EC 2.1.1.43 (Histone-Lysine N-Methyltransferase)
RN  - EC 2.7.11.24 (JNK Mitogen-Activated Protein Kinases)
SB  - IM
MH  - Amino Acid Motifs
MH  - Amino Acid Sequence
MH  - Animals
MH  - Binding Sites
MH  - Chromatin/metabolism
MH  - Crystallography, X-Ray
MH  - Fibroblasts
MH  - HEK293 Cells
MH  - Histone-Lysine N-Methyltransferase
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins/metabolism
MH  - JNK Mitogen-Activated Protein Kinases/metabolism
MH  - Mice
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Myeloid-Lymphoid Leukemia Protein/chemistry/*metabolism
MH  - Phosphorylation
MH  - Protein Binding
MH  - Protein Multimerization
MH  - Proto-Oncogene Proteins/*chemistry/*metabolism
MH  - Proto-Oncogene Proteins c-jun/chemistry/*metabolism
MH  - Structure-Activity Relationship
MH  - *Transcription, Genetic
PMC - PMC3983792
MID - NIHMS515115
EDAT- 2012/02/14 06:00
MHDA- 2012/03/30 06:00
PMCR- 2014/04/11
CRDT- 2012/02/14 06:00
PHST- 2011/07/17 00:00 [received]
PHST- 2011/12/19 00:00 [accepted]
PHST- 2012/02/14 06:00 [entrez]
PHST- 2012/02/14 06:00 [pubmed]
PHST- 2012/03/30 06:00 [medline]
PHST- 2014/04/11 00:00 [pmc-release]
AID - nature10806 [pii]
AID - 10.1038/nature10806 [doi]
PST - epublish
SO  - Nature. 2012 Feb 12;482(7386):542-6. doi: 10.1038/nature10806.