Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8.
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.
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.
Jianyun
J
Nie
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
Chao
C
Xu
Lunenfeld-tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada.
Jing
J
Jin
The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
Juliette A
JA
Aka
Structural Genomics Consortium, University of Toronto, 101 College Street, Toronto, ON M5G 1L7, Canada.
Wolfram
W
Tempel
Lunenfeld-tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada.
Vivian
V
Nguyen
The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
Linya
L
You
The Rosalind & Morris Goodman Cancer Research Center, Department of Medicine, McGill University, Montréal, QC H3A 1A3, Canada.
Ryan
R
Weist
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: jr.min@utoronto.ca.
Jinrong
J
Min
Lunenfeld-tanenbaum Research Institute, Toronto, ON M5G 1X5, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5G 1L7, Canada.
Tony
T
Pawson
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: xiang-jiao.yang@mcgill.ca.
Xiang-Jiao
XJ
Yang
D000595:Amino Acid Sequence; D017089:Ankyrin Repeat; D017487:Ankyrins / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002352:Carrier Proteins / Q000737:chemistry* / Q000378:metabolism; D044842:Cullin Proteins / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics / Q000378:metabolism*; D057809:HEK293 Cells; D006655:Histone Deacetylases / Q000378:metabolism; D006801:Humans; D008969:Molecular Sequence Data; D009123:Muscle Hypotonia / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D012097:Repressor Proteins / Q000378:metabolism; D013131:Spine / Q000002:abnormalities* / Q000378:metabolism
C419548:ANKRA2 protein, human; D017487:Ankyrins; C569196:CCDC8 protein, human; C506299:CUL7 protein, human; D002352:Carrier Proteins; D044842:Cullin Proteins; D003598:Cytoskeletal Proteins; C522000:OBSL1 protein, human; D012097:Repressor Proteins; C400300:HDAC4 protein, human; C404500:HDAC5 protein, human; D006655:Histone Deacetylases