Protein stability and transcription factor complex assembly determined by the SCL-LMO2 interaction.
Gene expression programs are established by networks of interacting transcription factors. The basic helix-loop-helix factor SCL and the LIM-only protein LMO2 are components of transcription factor complexes that are essential for hematopoiesis. Here we show that LMO2 and SCL are predominant interaction partners in hematopoietic cells and that this interaction occurs through a conserved interface residing in the loop and helix 2 of SCL. This interaction nucleates the assembly of SCL complexes on DNA and is required for target gene induction and for the stimulation of erythroid and megakaryocytic differentiation. We also demonstrate that SCL determines LMO2 protein levels in hematopoietic cells and reveal that interaction with SCL prevents LMO2 degradation by the proteasome. We propose that the SCL-LMO2 interaction couples protein stabilization with higher order protein complex assembly, thus providing a powerful means of modulating the stoichiometry and spatiotemporal activity of SCL complexes. This interaction likely provides a rate-limiting step in the transcriptional control of hematopoiesis and leukemia, and similar mechanisms may operate to control the assembly of diverse protein modules.
Lécuyer
Eric
E
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Larivière
Simon
S
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Sincennes
Marie-Claude
MC
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Haman
André
A
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Lahlil
Rachid
R
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Todorova
Margarita
M
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Tremblay
Mathieu
M
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada.
Wilkes
Brian C
BC
Institut de Recherche Clinique de Montréal, Montréal, Québec H2W 1R7, Canada.
Hoang
Trang
T
Institut de Recherche en Immunologie et Cancérologie and the Departments of, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Molecular Biology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Pharmacology, Université de Montréal, Montréal, Québec, H3C 2J7, Canada; Department of Biochemistry, Université de Montréal, Montréal, Québec H3C 2J7, Canada. Electronic address: Trang.hoang@umontreal.ca.
D048868:Adaptor Proteins, Signal Transducing; D000595:Amino Acid Sequence; D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002454:Cell Differentiation; D004268:DNA-Binding Proteins / Q000378:metabolism*; D006801:Humans; D060588:LIM Domain Proteins; D008533:Megakaryocytes / Q000378:metabolism; D008667:Metalloproteins / Q000378:metabolism*; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D041681:NIH 3T3 Cells; D011487:Protein Conformation; D011506:Proteins / Q000737:chemistry*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1
D048868:Adaptor Proteins, Signal Transducing; D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D060588:LIM Domain Proteins; D008667:Metalloproteins; D011506:Proteins; D011518:Proto-Oncogene Proteins; D000073942:T-Cell Acute Lymphocytic Leukemia Protein 1; C085117:LMO2 protein, human; C513188:Lmo2 protein, mouse; C489366:Tal1 protein, mouse; C067143:TAL1 protein, human