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ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTBackbone Dynamics of a Free and Phosphopeptide-Complexed Src Homology 2 Domain Studied by 15N NMR RelaxationNeil A. Farrow, Ranjith Muhandiram, Alex U. Singer, Steven M. Pascal, Cyril Kay, Gerry Gish, E. Shoelson, Tony Pawson, Julie D. Forman-Kay, Lewis KayCite this: Biochemistry 1994, 33, 19, 5984–6003Publication Date (Print):May 17, 1994Publication History Published online1 May 2002Published inissue 17...
Cells chemically isolate molecules in compartments to both facilitate and regulate their interactions. In addition membrane-encapsulated compartments, cells can form proteinaceous membraneless organelles, including nucleoli, Cajal PML bodies, stress granules. The principles that determine when why these structures have remained elusive. Here, we demonstrate the disordered tails of Ddx4, a primary constituent nuage or germ granules, phase-separated organelles live vitro. These bodies are...
Protein phase separation is implicated in formation of membraneless organelles, signaling puncta and the nuclear pore. Multivalent interactions modular binding domains their target motifs can drive separation. However, forces promoting more common intrinsically disordered regions are less understood, with suggested roles for multivalent cation-pi, pi-pi, charge hydrophobic effect. Known phase-separating proteins enriched pi-orbital containing residues thus we analyzed pi-interactions folded...
The synucleins are a family of intrinsically disordered proteins involved in various human diseases. alpha-Synuclein has been extensively characterized due to its role Parkinson's disease where it forms intracellular aggregates, while gamma-synuclein is overexpressed majority late-stage breast cancers. Despite fairly strong sequence similarity between the amyloid-forming regions alpha- and gamma-synuclein, only weak propensity form amyloid fibrils. We hypothesize that different fibrillation...
Significance The cell is divided into compartments where specific biochemical functions are performed. These can be delineated by membranes or through phase separation of proteins protein and nucleic acids to form membraneless organelles. latter situation occurs with an intrinsically disordered region Ddx4, a major constituent germ granules. nature the interior organelles poorly understood. Here, we use NMR show that Ddx4 remains highly dynamic in phase-separated state, while diffusing as...
15N relaxation dispersion experiments were applied to the isolated N-terminal SH3 domain of Drosophila protein drk (drkN SH3) study microsecond second time scale exchange processes. The drkN exists in equilibrium between folded (Fexch) and unfolded (Uexch) states under nondenaturing conditions a ratio 2:1 at 20 °C, with an average rate constant, kex, 2.2 s-1 (slow on NMR chemical shift scale). Consequently discrete set resonances is observed for each state spectra. Within Uexch ensemble...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTTwo-dimensional NMR experiments for correlating carbon-13.beta. and proton.delta./.epsilon. chemical shifts of aromatic residues in 13C-labeled proteins via scalar couplingsToshio Yamazaki, Julie D. Forman-Kay, Lewis E. KayCite this: J. Am. Chem. Soc. 1993, 115, 23, 11054–11055Publication Date (Print):November 1, 1993Publication History Published online1 May 2002Published inissue 1 November...
Intrinsically disordered proteins (IDPs), which lack folded structure and are under nondenaturing conditions, have been shown to perform important functions in a large number of cellular processes. These interesting structural properties that deviate from the random-coil-like behavior exhibited by chemically denatured proteins. In particular, IDPs often observed exhibit significant compaction. this study, we analyzed hydrodynamic radii investigate sequence determinants Net charge proline...
Intrinsically disordered proteins play critical but often poorly understood roles in mediating protein interactions. The interactions of studied to date typically entail structural stabilization, whether as a global disorder-to-order transition or minimal ordering short linear motifs. cyclin-dependent kinase (CDK) inhibitor Sic1 interacts with single site on its receptor Cdc4 only upon phosphorylation multiple dispersed CDK sites. molecular basis for this multisite-dependent interaction is...
Significance Activity-dependent translation, the reversible activation of translation in response to synaptic activity, is important for plasticity and long-term memory formation. How activity triggers silenced mRNAs within neuronal granules, which are membraneless RNA–protein assemblies, not clear. We show that C-terminal region Fragile X Mental Retardation Protein (FMRP), an abundant granule protein, phase separates vitro with RNA its separation fine-tuned by posttranslational...
Membraneless organelles involved in RNA processing are biomolecular condensates assembled by phase separation. Despite the important role of intrinsically disordered protein regions (IDRs), specific interactions underlying IDR separation and its functional consequences remain elusive. To address these questions, we used minimal formed from C-terminal two interacting translational regulators, FMRP CAPRIN1. Nuclear magnetic resonance spectroscopy FMRP-CAPRIN1 revealed involving arginine-rich...
Liquid-liquid phase separation of charge- and/or aromatic-enriched intrinsically disordered proteins (IDPs) is critical in the biological function membraneless organelles. Much physics this recent discovery remains to be elucidated. Here, we present a theory random approximation account for electrostatic effects polyampholyte separations, yielding predictions consistent with experiments on IDP Ddx4. The applicable any charge pattern and thus provides general analytical framework studying...
Endeavoring toward a transferable, predictive coarse-grained explicit-chain model for biomolecular condensates underlain by liquid-liquid phase separation (LLPS), we conducted multiple-chain simulations of the N-terminal intrinsically disordered region (IDR) DEAD-box helicase Ddx4, as test case, to assess roles electrostatic, hydrophobic, cation-$\pi$, and aromatic interactions in amino acid sequence-dependent LLPS. We evaluated 3 residue-residue interaction schemes with shared electrostatic...
Intrinsically disordered proteins (IDPs), which lack persistent structure, are a challenge to structural biology due the inapplicability of standard methods for characterization folded as well their deviation from dominant structure/function paradigm. Their widespread presence and involvement in biological function, however, has spurred growing acceptance importance IDPs development new tools studying dynamics, function. The interplay domains or regions function existence continuum protein...