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Sequence-specific recognition of a PxLPxI/L motif by an ankyrin repeat tumbler lock.

Xu C, Jin J, Bian C, Lam R, Tian R, Weist R, You L, Nie J, Bochkarev A, Tempel W, Tan CS, Wasney GA, Vedadi M, Gish GD, Arrowsmith CH, Pawson T, Yang XJ, Min J
Sci Signal 5 ra39 (2012)
Related entries: 3so8, 3uxg, 3v2o, 3v2x, 3v30, 3v31

Cited: 31 times
EuropePMC logo PMID: 22649097

Abstract

Ankyrin repeat family A protein 2 (ANKRA2) interacts with the plasma membrane receptor megalin and the class IIa histone deacetylases HDAC4 and HDAC5. We report that the ankyrin repeat domains of ANKRA2 and its close paralog regulatory factor X-associated ankyrin-containing protein (RFXANK) recognize a PxLPxI/L motif found in diverse binding proteins, including HDAC4, HDAC5, HDAC9, megalin, and regulatory factor X, 5 (RFX5). Crystal structures of the ankyrin repeat domain of ANKRA2 in complex with its binding peptides revealed that each of the middle three ankyrin repeats of ANKRA2 recognizes a residue from the PxLPxI/L motif in a tumbler-lock binding mode, with ANKRA2 acting as the lock and the linear binding motif serving as the key. Structural analysis showed that three disease-causing mutations in RFXANK affect residues that are critical for binding to RFX5. These results suggest a fundamental principle of longitudinal recognition of linear sequences by a repeat-type domain. In addition, phosphorylation of serine 350, a residue embedded within the PxLPxI/L motif of HDAC4, impaired the binding of ANKRA2 but generated a high-affinity docking site for 14-3-3 proteins, which may help sequester this HDAC in the cytoplasm. Thus, the binding preference of the PxLPxI/L motif is signal-dependent. Furthermore, proteome-wide screening suggested that a similar phosphorylation-dependent switch may operate in other pathways. Together, our findings uncover a previously uncharacterized sequence- and signal-dependent peptide recognition mode for a repeat-type protein domain.

Reviews - 3uzd mentioned but not cited (1)

  1. TSPO protein binding partners in bacteria, animals, and plants. Hiser C, Montgomery BL, Ferguson-Miller S. J Bioenerg Biomembr 53 463-487 (2021)

Articles - 3uzd mentioned but not cited (5)

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Reviews citing this publication (8)

  1. The Roles of Histone Deacetylases and Their Inhibitors in Cancer Therapy. Li G, Tian Y, Zhu WG. Front Cell Dev Biol 8 576946 (2020)
  2. Modular evolution of phosphorylation-based signalling systems. Jin J, Pawson T. Philos Trans R Soc Lond B Biol Sci 367 2540-2555 (2012)
  3. The ADAMs family of proteases as targets for the treatment of cancer. Mullooly M, McGowan PM, Crown J, Duffy MJ. Cancer Biol Ther 17 870-880 (2016)
  4. Innovative Strategies for Selective Inhibition of Histone Deacetylases. Maolanon AR, Madsen AS, Olsen CA. Cell Chem Biol 23 759-768 (2016)
  5. Modular peptide binding: from a comparison of natural binders to designed armadillo repeat proteins. Reichen C, Hansen S, Plückthun A. J Struct Biol 185 147-162 (2014)
  6. Poxviral ANKR/F-box Proteins: Substrate Adapters for Ubiquitylation and More. Ingham RJ, Loubich Facundo F, Dong J. Pathogens 11 875 (2022)
  7. Structural aspects of the MHC expression control system. Nash G, Paidimuddala B, Zhang L. Biophys Chem 284 106781 (2022)
  8. HDAC4 Inhibitors as Antivascular Senescence Therapeutics. Huang C, Lin Z, Liu X, Ding Q, Cai J, Zhang Z, Rose P, Zhu YZ. Oxid Med Cell Longev 2022 3087916 (2022)

Articles citing this publication (17)

  1. Identification of a Novel Sequence Motif Recognized by the Ankyrin Repeat Domain of zDHHC17/13 S-Acyltransferases. Lemonidis K, Sanchez-Perez MC, Chamberlain LH. J Biol Chem 290 21939-21950 (2015)
  2. Structural basis of diverse membrane target recognitions by ankyrins. Wang C, Wei Z, Chen K, Ye F, Yu C, Bennett V, Zhang M. Elife 3 (2014)
  3. Tudor domains of the PRC2 components PHF1 and PHF19 selectively bind to histone H3K36me3. Qin S, Guo Y, Xu C, Bian C, Fu M, Gong S, Min J. Biochem Biophys Res Commun 430 547-553 (2013)
  4. Peptide array-based screening reveals a large number of proteins interacting with the ankyrin-repeat domain of the zDHHC17 S-acyltransferase. Lemonidis K, MacLeod R, Baillie GS, Chamberlain LH. J Biol Chem 292 17190-17202 (2017)
  5. TIMP3 controls cell fate to confer hepatocellular carcinoma resistance. Defamie V, Sanchez O, Murthy A, Khokha R. Oncogene 34 4098-4108 (2015)
  6. Ankyrin repeats of ANKRA2 recognize a PxLPxL motif on the 3M syndrome protein CCDC8. Nie J, Xu C, Jin J, Aka JA, Tempel W, Nguyen V, You L, Weist R, Min J, Pawson T, Yang XJ. Structure 23 700-712 (2015)
  7. Structural Mimicry by a Bacterial F Box Effector Hijacks the Host Ubiquitin-Proteasome System. Wong K, Perpich JD, Kozlov G, Cygler M, Abu Kwaik Y, Gehring K. Structure 25 376-383 (2017)
  8. Myosin III-mediated cross-linking and stimulation of actin bundling activity of Espin. Liu H, Li J, Li J, Raval MH, Yao N, Deng X, Lu Q, Nie S, Feng W, Wan J, Yengo CM, Liu W, Zhang M. Elife 5 e12856 (2016)
  9. Molecular basis for arginine C-terminal degron recognition by Cul2FEM1 E3 ligase. Chen X, Liao S, Makaros Y, Guo Q, Zhu Z, Krizelman R, Dahan K, Tu X, Yao X, Koren I, Xu C. Nat Chem Biol 17 254-262 (2021)
  10. Chimeric 14-3-3 proteins for unraveling interactions with intrinsically disordered partners. Sluchanko NN, Tugaeva KV, Greive SJ, Antson AA. Sci Rep 7 12014 (2017)
  11. Structural basis for the recognition of kinesin family member 21A (KIF21A) by the ankyrin domains of KANK1 and KANK2 proteins. Guo Q, Liao S, Zhu Z, Li Y, Li F, Xu C. J Biol Chem 293 557-566 (2018)
  12. Ankyrin repeats in context with human population variation. Utgés JS, Tsenkov MI, Dietrich NJM, MacGowan SA, Barton GJ. PLoS Comput Biol 17 e1009335 (2021)
  13. Chloroplast PetD protein: evidence for SRP/Alb3-dependent insertion into the thylakoid membrane. Króliczewski J, Bartoszewski R, Króliczewska B. BMC Plant Biol 17 213 (2017)
  14. Ankyrin2 is essential for neuronal morphogenesis and long-term courtship memory in Drosophila. Schwartz S, Wilson SJ, Hale TK, Fitzsimons HL. Mol Brain 16 42 (2023)
  15. A PCR-free rapid protocol for one-pot construction of highly diverse genetic libraries. Woolley M, Chen Z. PLoS One 17 e0276338 (2022)
  16. Deciphering the roles of subcellular distribution and interactions involving the MEF2 binding region, the ankyrin repeat binding motif and the catalytic site of HDAC4 in Drosophila neuronal morphogenesis. Tan WJ, Hawley HR, Wilson SJ, Fitzsimons HL. BMC Biol 22 2 (2024)
  17. The KLDpT activation loop motif is critical for MARK kinase activity. Sonntag T, Moresco JJ, Yates JR, Montminy M. PLoS One 14 e0225727 (2019)


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