Structure
Volume 23, Issue 4, 7 April 2015, Pages 700-712
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Article
Ankyrin Repeats of ANKRA2 Recognize a PxLPxL Motif on the 3M Syndrome Protein CCDC8

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Highlights

  • The 3M syndrome protein CCDC8 is a top binder of the ankyrin-repeat protein ANKRA2

  • ANKRA2 recognizes a PxLPxL motif located at the C-terminal domain of CCDC8

  • The N-terminal domain of CCDC8 interacts with two other 3M syndrome proteins

  • 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.

Cited by (0)

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Co-first author

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Present address: Department of Medicine-Nephrology/Hypertension, Northwestern University, 320 East Superior Street Searle 10-521, Chicago, IL 60611, USA

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The author passed away unexpectedly in 2013