The 3M syndrome protein CCDC8 is a top binder of the ankyrin-repeat protein ANKRA2
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ANKRA2 recognizes a PxLPxL motif located at the C-terminal domain of CCDC8
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The N-terminal domain of CCDC8 interacts with two other 3M syndrome proteins
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ANKRA2 binds HDAC4 and HDAC5 to block the interaction with CUL7
Summary
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.
Present address: Department of Medicine-Nephrology/Hypertension, Northwestern University, 320 East Superior Street Searle 10-521, Chicago, IL 60611, USA