BH3-ligand regulates access of MCL-1 to its E3 ligase.
A genome wide search for new BH3-containing Bcl-2 family members was conducted using position weight matrices (PWM) and identified a large (480kDa), novel BH3-only protein, originally called LASU1 (now also known as Ureb-1, E3(histone), ARF-BP1, and Mule). We demonstrated that LASU1 is an E3 ligase that ubiquitinated Mcl-1 in vitro and was required for its proteasome-dependent degradation in HeLa cells. Of note, the BH3 domain of LASU1 interacted with Mcl-1 but not with Bcl-2 or Bcl-Xl. A competing BH3-ligand derived from Bim interacted with Mcl-1 and prevented its interaction with LASU1 in HeLa cells, causing elevation of the steady-state levels of Mcl-1. This suggests that the unliganded form of Mcl-1 is sensitive to LASU1-mediated degradation of Mcl-1.
Warr
Matthew R
MR
Department of Biochemistry, McIntyre Medical Sciences Building, McGill University, Montréal, Que., Canada.
Acoca
Stephane
S
Liu
Zhiqian
Z
Germain
Marc
M
Watson
Mark
M
Blanchette
Mathieu
M
Wing
Simon S
SS
Shore
Gordon C
GC
D000595:Amino Acid Sequence; D002478:Cells, Cultured; D019295:Computational Biology; D006801:Humans; D008024:Ligands; D008969:Molecular Sequence Data; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D025521:Tumor Suppressor Proteins; D044767:Ubiquitin-Protein Ligases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D014452:Ubiquitins / Q000378:metabolism
D008024:Ligands; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009363:Neoplasm Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D025521:Tumor Suppressor Proteins; D014452:Ubiquitins; C502830:HUWE1 protein, human; D044767:Ubiquitin-Protein Ligases