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Autoinhibition of X11/Mint scaffold proteins revealed by the closed conformation of the PDZ tandem.

Long JF, Feng W, Wang R, Chan LN, Ip FC, Xia J, Ip NY, Zhang M
Nat Struct Mol Biol 12 722-8 (2005)
Related entries: 1u37, 1u39, 1u3b

Cited: 53 times
EuropePMC logo PMID: 16007100

Abstract

Members of the X11/Mint family of multidomain adaptor proteins are composed of a divergent N terminus, a conserved PTB domain and a pair of C-terminal PDZ domains. Many proteins can interact with the PDZ tandem of X11 proteins, although the mechanism of such interactions is unclear. Here we show that the highly conserved C-terminal tail of X11alpha folds back and inserts into the target-binding groove of the first PDZ domain. The binding of this tail occludes the binding of other target peptides. This autoinhibited conformation of X11 requires that the two PDZ domains and the entire C-terminal tail be covalently connected to form an integral structural unit. The autoinhibited conformation of the X11 PDZ tandem provides a mechanistic explanation for the unique target-binding properties of the protein and hints at potential regulatory mechanisms for the X11-target interactions.

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  1. Putting into practice domain-linear motif interaction predictions for exploration of protein networks. Luck K, Fournane S, Kieffer B, Masson M, Nominé Y, Travé G. PLoS One 6 e25376 (2011)


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  2. Dynamic control of signaling by modular adaptor proteins. Pawson T. Curr Opin Cell Biol 19 112-116 (2007)
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  5. Plasticity of PDZ domains in ligand recognition and signaling. Ivarsson Y. FEBS Lett 586 2638-2647 (2012)
  6. The emerging contribution of sequence context to the specificity of protein interactions mediated by PDZ domains. Luck K, Charbonnier S, Travé G. FEBS Lett 586 2648-2661 (2012)
  7. The X11/Mint family of adaptor proteins. Rogelj B, Mitchell JC, Miller CC, McLoughlin DM. Brain Res Rev 52 305-315 (2006)
  8. PDZ Domains as Drug Targets. Christensen NR, Čalyševa J, Fernandes EFA, Lüchow S, Clemmensen LS, Haugaard-Kedström LM, Strømgaard K. Adv Ther (Weinh) 2 1800143 (2019)
  9. Structural diversity of PDZ-lipid interactions. Gallardo R, Ivarsson Y, Schymkowitz J, Rousseau F, Zimmermann P. Chembiochem 11 456-467 (2010)
  10. Synaptic transmission regulated by a presynaptic MALS/Liprin-alpha protein complex. Olsen O, Moore KA, Nicoll RA, Bredt DS. Curr Opin Cell Biol 18 223-227 (2006)
  11. Synapse formation and remodeling. Luo Z. Sci China Life Sci 53 315-321 (2010)
  12. Scaffold proteins as dynamic integrators of biological processes. DiRusso CJ, Dashtiahangar M, Gilmore TD. J Biol Chem 298 102628 (2022)
  13. Targeting PDZ domains as potential treatment for viral infections, neurodegeneration and cancer. Nardella C, Visconti L, Malagrinò F, Pagano L, Bufano M, Nalli M, Coluccia A, La Regina G, Silvestri R, Gianni S, Toto A. Biol Direct 16 15 (2021)

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