Scaffold proteins as dynamic switches.

نویسنده

  • Mingjie Zhang
چکیده

often assembled into their supramolecular complexes and targeted to specific regions of cells by multimodular scaffold proteins. The success of this organization and localization is critical for signaling efficiency and specificity. The catalytically inactive scaffold proteins that perform these tasks are traditionally viewed as passive molecules that " glue " signaling proteins together. However, research in a recent article by Mishra et al. 1 reveals that one of the PDZ domains in the fruit fly photoreceptor scaffold protein INAD can cycle between two functionally distinct conformations in a light-dependent manner and actively participates in the G protein–coupled visual signaling process. PDZ domain scaffold proteins are highly abundant in eukaryotic genomes. Each PDZ domain contains ~90 residues and folds into a globular module capable of binding to short peptide fragments situated at the extreme carboxyl tail of target proteins. INAD uses its five PDZ domains to assemble the core proteins required for fruit fly visual signal transduction 2,3. The scaffolding of the Ca 2+-permeable transient receptor potential (TRP) channel, phospholipase C and eye-specific protein kinase C (PKC) to INAD at the inner membrane surface of Drosophila melanogas-ter photoreceptor cells efficiently links the G protein–coupled receptor rhodopsin (the photon detector) with the Ca 2+-mediated second messenger signaling processes. PKC in the INAD-organized complex has a key role in the termination of the light stimulation signal by negative feedback inhibition of the TRP channel. To learn more about the structure and function of INAD, Mishra et al. 1 solved the crystal structure of the fifth PDZ domain in INAD in the absence of reducing reagent; surprisingly, they discovered a stable disulfide bond formed between two cysteines in the αB-helix and the βB-strand near the bottom of the canonical target-binding groove (Fig. 1a). In this oxidized PDZ5, the target-binding groove is severely deformed, apparently because of the melting of the C-terminal half of the αB-helix normally seen in canonical PDZ domains. The authors also crystallized PDZ5 in the presence of 10 mM DTT and unexpectedly found that reduced and oxidized states coexist within each asymmetric unit. The binding groove of the reduced form of PDZ5 adopts the canoni-cal conformation of PDZ domains, and thus is predicted to be able to bind to target proteins (Fig. 1a). Together with additional biochemical data, the authors concluded that PDZ5 exists in equilibrium between the two structural states, likely with distinct target binding activities in each conformation. Looking …

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عنوان ژورنال:
  • Nature chemical biology

دوره 3 12  شماره 

صفحات  -

تاریخ انتشار 2007