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High levels of structural disorder in scaffold proteins as exemplified by a novel neuronal protein, CASK-interactive protein1.
FEBS J. 2009 Jul; 276(14):3744-56
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22 Oct 2009
Confirmation, Interesting Hypothesis, New Finding
DOI: 10.3410/f.1165386.628355
I have found this article interesting because it illustrates a crucial role of intrinsic disorder in the function of crucial regulators of signaling pathways, scaffold proteins. It will be of interest to everyone studying large multiprotein complexes, their assembly and regulation.
Scaffold proteins...Continue reading
Scaffold proteins...Continue reading
I have found this article interesting because it illustrates a crucial role of intrinsic disorder in the function of crucial regulators of signaling pathways, scaffold proteins. It will be of interest to everyone studying large multiprotein complexes, their assembly and regulation.
Scaffold proteins are very important players in various signaling pathways, where they interact with multiple pathway members, tethering them into functional complexes, localizing these signaling components to specific areas of the cell, regulating signal transduction by coordinating positive and negative feedback signals, and insulating correct signaling proteins from competing proteins {1}. To better understand the molecular mechanism of scaffold action, the authors characterized the functional and structural properties of the C-terminal proline-rich region of the CASK-interactive protein 1 (Caskin 1). Caskin 1 is a member of the recently discovered family of neuronal scaffold proteins {2}. Its N-terminal half possesses six ankyrin repeats, two sterile alpha motifs (SAM domains) and a single SH3 domain, whereas its C-terminal half (~800 residues), being proline-rich, lacks detectable sequence homology to any previously characterized protein or domain. The authors showed that Caskin1 can physically interact with 11 different partners all involved in signal transduction, including Abl-interactor-2 (Abi2), CASK (also known as kappa-casein), EphA2, L1CAM, Myosin-IB, Nck1, Neurexin-2, Stathmin-like 3 protein, Synaptotagmin, Septin-4, and Siah1. Importantly, the thorough biophysical and computational characterization revealed that the C-terminal proline-rich region of Caskin1, being crucial for protein function, lacks ordered structure and therefore belongs to the class of intrinsically disordered proteins (IDPs). At the next stage, the authors collected 74 scaffold proteins and characterized them by the different predictors of intrinsic disorder. This analysis revealed that the frequency of disorder in these proteins was very high: on average, ~55% of their amino acids were predicted to be localized in disordered regions. On the other hand, disorder was not evenly distributed in the sequences, suggesting that the overall topology of scaffold proteins resembles beads on a string, where relatively short globular domains are connected by very long linker regions. Based on these observations it has been concluded that intrinsic disorder is highly abundant in scaffold proteins and potentially plays crucial roles in the function of these important regulators of signaling pathways. Intersetingly, these findings happen to provide support to the hypothesis proposed in a recent review which I co-authored {3}, where, based on the analysis of data available for several well-known scaffold proteins and their partners, it has been concluded that intrinsic disorder is crucial for scaffold function and enhances this function by a wide variety of mechanisms.
Scaffold proteins are very important players in various signaling pathways, where they interact with multiple pathway members, tethering them into functional complexes, localizing these signaling components to specific areas of the cell, regulating signal transduction by coordinating positive and negative feedback signals, and insulating correct signaling proteins from competing proteins {1}. To better understand the molecular mechanism of scaffold action, the authors characterized the functional and structural properties of the C-terminal proline-rich region of the CASK-interactive protein 1 (Caskin 1). Caskin 1 is a member of the recently discovered family of neuronal scaffold proteins {2}. Its N-terminal half possesses six ankyrin repeats, two sterile alpha motifs (SAM domains) and a single SH3 domain, whereas its C-terminal half (~800 residues), being proline-rich, lacks detectable sequence homology to any previously characterized protein or domain. The authors showed that Caskin1 can physically interact with 11 different partners all involved in signal transduction, including Abl-interactor-2 (Abi2), CASK (also known as kappa-casein), EphA2, L1CAM, Myosin-IB, Nck1, Neurexin-2, Stathmin-like 3 protein, Synaptotagmin, Septin-4, and Siah1. Importantly, the thorough biophysical and computational characterization revealed that the C-terminal proline-rich region of Caskin1, being crucial for protein function, lacks ordered structure and therefore belongs to the class of intrinsically disordered proteins (IDPs). At the next stage, the authors collected 74 scaffold proteins and characterized them by the different predictors of intrinsic disorder. This analysis revealed that the frequency of disorder in these proteins was very high: on average, ~55% of their amino acids were predicted to be localized in disordered regions. On the other hand, disorder was not evenly distributed in the sequences, suggesting that the overall topology of scaffold proteins resembles beads on a string, where relatively short globular domains are connected by very long linker regions. Based on these observations it has been concluded that intrinsic disorder is highly abundant in scaffold proteins and potentially plays crucial roles in the function of these important regulators of signaling pathways. Intersetingly, these findings happen to provide support to the hypothesis proposed in a recent review which I co-authored {3}, where, based on the analysis of data available for several well-known scaffold proteins and their partners, it has been concluded that intrinsic disorder is crucial for scaffold function and enhances this function by a wide variety of mechanisms.
References
1.
Scaffold proteins and immune-cell signalling.
Nat Rev Immunol 2009 Jan; 1(9):47-56
PMID: 19104498
2.
CASK participates in alternative tripartite complexes in which Mint 1 competes for binding with caskin 1, a novel CASK-binding protein.
J Neurosci 2002 Jun 1; 11(22):4264-73
PMID: 12040031
3.
Intrinsic disorder in scaffold proteins: getting more from less.
Prog Biophys Mol Biol 2008 Sep; 1(98):85-106
PMID: 18619997
Disclosures
None declared
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Uversky V: F1000Prime Recommendation of [Balázs A et al., FEBS J 2009, 276(14):3744-56]. In F1000Prime, 22 Oct 2009; DOI: 10.3410/f.1165386.628355. F1000Prime.com/1165386#eval628355
F1000Prime Recommendations, Dissents and Comments for [Balázs A et al., FEBS J 2009, 276(14):3744-56]. In F1000Prime, 24 May 2013; F1000Prime.com/1165386
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CASK-interactive protein1 is a newly recognized post-synaptic density protein in mammalian neurons. Although its N-terminal region contains several well-known functional domains, its entire C-terminal proline-rich region of 800 amino acids lacks detectable sequence homology to any previously characterized protein. We used multiple techniques for the structural characterization of this region and its three fragments. By bioinformatics predictions, CD spectroscopy, wide-line and 1H-NMR spectroscopy, limited proteolysis and gel filtration chromatography, we provided evidence that the entire proline-rich region of CASK-interactive protein1 is intrinsically disordered. We also showed that the proline-rich region is biochemically functional, as it interacts with the adaptor protein Abl-interactor-2. To extend the finding of a high level of disorder in this scaffold protein, we collected 74 scaffold proteins (also including proteins denoted as anchor and docking), and predicted their disorder by three different algorithms. We found that a very high fraction (53.6; on average) of the residues fall into local disorder and their ordered domains are connected by linker regions which are mostly disordered (64.5 on average). Because of this high frequency of disorder, the usual design of scaffold proteins of short globular domains (86 amino acids on average) connected by longer linker regions (140 amino acids on average) and the noted binding functions of these regions in both CASK-interactive protein1 and the other proteins studied, we suggest that structurally disordered regions prevail and play key recognition roles in scaffold proteins.
DOI: 10.1111/j.1742-4658.2009.07090.x
PMID: 19523119
