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

Jianyun Nie, Chao Xu, Jing Jin, Juliette A. Aka, Wolfram Tempel, Vivian Nguyen, Linya You, Ryan Weist, Jinrong Min*, Tony Pawson, Xiang Jiao Yang

*Corresponding author for this work

Research output: Contribution to journalArticle

4 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)700-712
Number of pages13
JournalStructure
Volume23
Issue number4
DOIs
StatePublished - Apr 7 2015

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Ankyrin Repeat
Histone Deacetylases
Ligases
Low Density Lipoprotein Receptor-Related Protein-2
Severe Combined Immunodeficiency
Ubiquitin
Cytoskeleton
Genes
Proteins
Transcription Factors
Peptides
Miller-McKusick-Malvaux-Syndrome (3M Syndrome)

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

Cite this

Nie, J., Xu, C., Jin, J., Aka, J. A., Tempel, W., Nguyen, V., ... Yang, X. J. (2015). Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8. Structure, 23(4), 700-712. https://doi.org/10.1016/j.str.2015.02.001
Nie, Jianyun ; Xu, Chao ; Jin, Jing ; Aka, Juliette A. ; Tempel, Wolfram ; Nguyen, Vivian ; You, Linya ; Weist, Ryan ; Min, Jinrong ; Pawson, Tony ; Yang, Xiang Jiao. / Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8. In: Structure. 2015 ; Vol. 23, No. 4. pp. 700-712.
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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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Nie, J, Xu, C, Jin, J, Aka, JA, Tempel, W, Nguyen, V, You, L, Weist, R, Min, J, Pawson, T & Yang, XJ 2015, 'Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8', Structure, vol. 23, no. 4, pp. 700-712. https://doi.org/10.1016/j.str.2015.02.001

Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8. / Nie, Jianyun; Xu, Chao; Jin, Jing; Aka, Juliette A.; Tempel, Wolfram; Nguyen, Vivian; You, Linya; Weist, Ryan; Min, Jinrong; Pawson, Tony; Yang, Xiang Jiao.

In: Structure, Vol. 23, No. 4, 07.04.2015, p. 700-712.

Research output: Contribution to journalArticle

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AU - Nie, Jianyun

AU - Xu, Chao

AU - Jin, Jing

AU - Aka, Juliette A.

AU - Tempel, Wolfram

AU - Nguyen, Vivian

AU - You, Linya

AU - Weist, Ryan

AU - Min, Jinrong

AU - Pawson, Tony

AU - Yang, Xiang Jiao

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N2 - 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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