PMID- 21757704
OWN - NLM
STAT- MEDLINE
DCOM- 20111205
LR  - 20211020
IS  - 1083-351X (Electronic)
IS  - 0021-9258 (Print)
IS  - 0021-9258 (Linking)
VI  - 286
IP  - 36
DP  - 2011 Sep 9
TI  - Crystal structure of menin reveals binding site for mixed lineage leukemia (MLL) 
      protein.
PG  - 31742-8
LID - 10.1074/jbc.M111.258186 [doi]
AB  - Menin is a tumor suppressor protein that is encoded by the MEN1 (multiple 
      endocrine neoplasia 1) gene and controls cell growth in endocrine tissues. 
      Importantly, menin also serves as a critical oncogenic cofactor of MLL (mixed 
      lineage leukemia) fusion proteins in acute leukemias. Direct association of menin 
      with MLL fusion proteins is required for MLL fusion protein-mediated 
      leukemogenesis in vivo, and this interaction has been validated as a new 
      potential therapeutic target for development of novel anti-leukemia agents. Here, 
      we report the first crystal structure of menin homolog from Nematostella 
      vectensis. Due to a very high sequence similarity, the Nematostella menin is a 
      close homolog of human menin, and these two proteins likely have very similar 
      structures. Menin is predominantly an alpha-helical protein with the protein core 
      comprising three tetratricopeptide motifs that are flanked by two alpha-helical 
      bundles and covered by a beta-sheet motif. A very interesting feature of menin 
      structure is the presence of a large central cavity that is highly conserved 
      between Nematostella and human menin. By employing site-directed mutagenesis, we 
      have demonstrated that this cavity constitutes the binding site for MLL. Our data 
      provide a structural basis for understanding the role of menin as a tumor 
      suppressor protein and as an oncogenic co-factor of MLL fusion proteins. It also 
      provides essential structural information for development of inhibitors targeting 
      the menin-MLL interaction as a novel therapeutic strategy in MLL-related 
      leukemias.
FAU - Murai, Marcelo J
AU  - Murai MJ
AD  - Department of Pathology, University of Michigan, Ann Arbor, Michigan 48109, USA.
FAU - Chruszcz, Maksymilian
AU  - Chruszcz M
FAU - Reddy, Gireesh
AU  - Reddy G
FAU - Grembecka, Jolanta
AU  - Grembecka J
FAU - Cierpicki, Tomasz
AU  - Cierpicki T
LA  - eng
SI  - PDB/3RE2
GR  - R01 CA160467/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20110713
PL  - United States
TA  - J Biol Chem
JT  - The Journal of biological chemistry
JID - 2985121R
RN  - 0 (MEN1 protein, human)
RN  - 0 (Proto-Oncogene Proteins)
RN  - 0 (Tumor Suppressor Proteins)
RN  - 149025-06-9 (Myeloid-Lymphoid Leukemia Protein)
SB  - IM
MH  - Animals
MH  - Binding Sites
MH  - Crystallography, X-Ray
MH  - Humans
MH  - Mutagenesis, Site-Directed
MH  - Myeloid-Lymphoid Leukemia Protein/chemistry/*metabolism
MH  - Protein Conformation
MH  - Protein Structure, Secondary
MH  - Proto-Oncogene Proteins/*chemistry/genetics/metabolism
MH  - Sea Anemones
MH  - Sequence Homology, Amino Acid
MH  - Tumor Suppressor Proteins
PMC - PMC3173070
EDAT- 2011/07/16 06:00
MHDA- 2011/12/13 00:00
PMCR- 2012/09/09
CRDT- 2011/07/16 06:00
PHST- 2011/07/16 06:00 [entrez]
PHST- 2011/07/16 06:00 [pubmed]
PHST- 2011/12/13 00:00 [medline]
PHST- 2012/09/09 00:00 [pmc-release]
AID - S0021-9258(20)72282-9 [pii]
AID - M111.258186 [pii]
AID - 10.1074/jbc.M111.258186 [doi]
PST - ppublish
SO  - J Biol Chem. 2011 Sep 9;286(36):31742-8. doi: 10.1074/jbc.M111.258186. Epub 2011 
      Jul 13.