Structural Basis of the Interaction of the Breast Cancer Oncogene LMO4 with the Tumour Suppressor CtIP/RBBP8

LIM-only protein 4 (LMO4) is strongly linked to the progression of breast cancer. Although the mechanisms underlying this phenomenon are not well understood, a role is emerging for LMO4 in regulation of the cell cycle. We determined the solution structure of LMO4 in complex with CtIP (C-terminal binding protein interacting protein)/RBBP8, a tumour suppressor protein that is involved in cell cycle progression, DNA repair and transcriptional regulation. Our data reveal that CtIP and the essential LMO cofactor LDB1 (LIM-domain binding protein 1) bind to the same face on LMO4 and cannot simultaneously bind to LMO4. We hypothesise that overexpression of LMO4 may disrupt some of the normal tumour suppressor activities of CtIP, thereby contributing to breast cancer progression.

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► LMO4 is overexpressed in breast cancer and can bind cell cycle control protein CtIP.
► LMO4 cannot bind CtIP and key partner LDB1 simultaneously.
► CtIP interacts with LMO4 using a short domain that forms an extended conformation on binding.
► The structure of a CtIP:LMO4 complex reveals similarity in LMO4–LDB1/CtIP binding.
► Excess LMO4 in cancer may sequester CtIP and may influence cell cycle control.