Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8

Structure. 2015 Apr 7;23(4):700-12. doi: 10.1016/j.str.2015.02.001.

Jianyun Nie ¹, Chao Xu ², Jing Jin ³, Juliette A Aka ⁴, Wolfram Tempel ², Vivian Nguyen ³, Linya You ⁴, Ryan Weist ⁴, Jinrong Min ⁵, Tony Pawson ⁶, Xiang-Jiao Yang ⁷

Affiliations

1 The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada; Department of Breast Cancer, The Third Affiliated Hospital, Kunming Medical University, Yunnan 650118, China.
2 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
3 Lunenfeld-tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada.
4 The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
5 Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada; Department of Physiology, University of Toronto, Toronto, ON M5S 1A8, Canada. Electronic address: [email protected].
6 Lunenfeld-tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
7 The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada; Department of Biochemistry, McGill University, Montréal, QC H3A 1A3, Canada; McGill University Health Center, Montréal, QC H3A 1A3, Canada. Electronic address: [email protected].

PMID: 25752541 DOI: 10.1016/j.str.2015.02.001

Abstract

Peptide motifs are often used for protein-protein interactions. We have recently demonstrated that ankyrin repeats of ANKRA2 and the paralogous bare lymphocyte syndrome transcription factor RFXANK recognize PxLPxL/I motifs shared by megalin, three histone deacetylases, and RFX5. We show here that that CCDC8 is a major partner of ANKRA2 but not RFXANK in cells. The CCDC8 gene is mutated in 3M syndrome, a short-stature disorder with additional facial and skeletal abnormalities. Two other genes mutated in this syndrome encode CUL7 and OBSL1. While CUL7 is a ubiquitin ligase and OBSL1 associates with the Cytoskeleton, little is known about CCDC8. Binding and structural analyses reveal that the ankyrin repeats of ANKRA2 recognize a PxLPxL motif at the C-terminal region of CCDC8. The N-terminal part interacts with OBSL1 to form a CUL7 ligase complex. These results link ANKRA2 unexpectedly to 3M syndrome and suggest novel regulatory mechanisms for histone deacetylases and RFX7.

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