Intrinsic Disorder and Functional Proteomics

Radivojac, Predrag; Iakoucheva, Lilia M.; Oldfield, Christopher J.; Obradović, Zoran; Uversky, Vladimir N.; Dunker, A. Keith

doi:10.1529/biophysj.106.094045

Cited by 654 publications

(618 citation statements)

References 204 publications

(229 reference statements)

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“…Characterization of the intrinsic disorder in human proteins associated with the PCD Analysis of the compositional biases in human PCD-related proteins: At the amino-acid composition level, IDPs/IDPRs are significantly depleted in order-promoting amino acids, C, W, I, Y, F, L, H, V, and N, and substantially enriched in disorder-promoting residues, A, G, R, T, S, K, Q, E, and P. 31 Figure 2a shows that the PCD-related human proteins are depleted in some major order-promoting residues and enriched in some major disorder-promoting residues, suggesting that these proteins might contain multiple signatures characteristic for the IDPs.…”

Section: Resultsmentioning

confidence: 99%

“…Amino-acid types are ranked according to their increasing disorder-promoting potential. 31 (b) Abundance of predicted long disordered regions in human PCD proteins (apoptosis, red bars; autophagy, green bars; and necroptosis, yellow bars) in comparison with long disordered regions in 2329 proteins involved in cellular signaling (AfCS, black bars), 53 630 eukaryotic proteins from SWISS-PROT (EU_SW, blue bars), and 1138 sequences corresponding to ordered parts of proteins from PDB Select 25 (O_PDB_S25, pink bars). (c) Distribution of the length of the disordered segments in human PCD-related proteins (apoptosis, red bars; autophagy, green bars; and necroptosis, yellow bars).…”

Section: Resultsmentioning

confidence: 99%

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Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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It is recognized now that intrinsically disordered proteins (IDPs), which do not have unique 3D structures as a whole or in noticeable parts, constitute a significant fraction of any given proteome. IDPs are characterized by an astonishing structural and functional diversity that defines their ability to be universal regulators of various cellular pathways. Programmed cell death (PCD) is one of the most intricate cellular processes where the cell uses specialized cellular machinery and intracellular programs to kill itself. This cell-suicide mechanism enables metazoans to control cell numbers and to eliminate cells that threaten the animal's survival. PCD includes several specific modules, such as apoptosis, autophagy, and programmed necrosis (necroptosis). These modules are not only tightly regulated but also intimately interconnected and are jointly controlled via a complex set of protein-protein interactions. To understand the role of the intrinsic disorder in controlling and regulating the PCD, several large sets of PCD-related proteins across 28 species were analyzed using a wide array of modern bioinformatics tools. This study indicates that the intrinsic disorder phenomenon has to be taken into consideration to generate a complete picture of the interconnected processes, pathways, and modules that determine the essence of the PCD. We demonstrate that proteins involved in regulation and execution of PCD possess substantial amount of intrinsic disorder. We annotate functional roles of disorder across and within apoptosis, autophagy, and necroptosis processes. Disordered regions are shown to be implemented in a number of crucial functions, such as protein-protein interactions, interactions with other partners including nucleic acids and other ligands, are enriched in post-translational modification sites, and are characterized by specific evolutionary patterns. We mapped the disorder into an integrated network of PCD pathways and into the interactomes of selected proteins that are involved in the p53-mediated apoptotic signaling pathway.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

et al. 2013

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“…The molecular mechanism behind their function is not yet established. From studies of other systems, it has become apparent that, despite the lack of a fixed three-dimensional structure, disordered proteins are often involved in key cellular processes such as signal transduction and stabilization of both proteins and RNA (Tompa, 2002;Dyson and Wright, 2005;Fink, 2005;Radivojac et al, 2007;Dunker et al, 2008;Uversky and Dunker, 2010). Binding of a disordered protein typically induces folding and activation (Mohan et al, 2006;Tompa and Fuxreiter, 2008;Wright and Dyson, 2009).…”

Section: Introductionmentioning

confidence: 99%

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

et al. 2011

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Dehydrins are intrinsically disordered plant proteins whose expression is upregulated under conditions of desiccation and cold stress. Their molecular function in ensuring plant survival is not yet known, but several studies suggest their involvement in membrane stabilization. The dehydrins are characterized by a broad repertoire of conserved and repetitive sequences, out of which the archetypical K-segment has been implicated in membrane binding. To elucidate the molecular mechanism of these K-segments, we examined the interaction between lipid membranes and a dehydrin with a basic functional sequence composition: Lti30, comprising only K-segments. Our results show that Lti30 interacts electrostatically with vesicles of both zwitterionic (phosphatidyl choline) and negatively charged phospholipids (phosphatidyl glycerol, phosphatidyl serine, and phosphatidic acid) with a stronger binding to membranes with high negative surface potential. The membrane interaction lowers the temperature of the main lipid phase transition, consistent with Lti30's proposed role in cold tolerance. Moreover, the membrane binding promotes the assembly of lipid vesicles into large and easily distinguishable aggregates. Using these aggregates as binding markers, we identify three factors that regulate the lipid interaction of Lti30 in vitro: (1) a pH dependent His on/off switch, (2) phosphorylation by protein kinase C, and (3) reversal of membrane binding by proteolytic digest.

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“…These unstructured regions are often essential for protein function. A large number of algorithms have been developed to predict regions of disorder from the amino acid sequence of a protein, commonly based on the initial finding that low hydrophobicity and high net charge is a defining feature of disordered proteins [138,139]. In mammals, 75% of signaling proteins and 50% of all cellular proteins are predicted to have regions with disorder of more than 30 amino acids in length.…”

Section: Disordered Proteins and Protein Segments Are Crucial For Celmentioning

confidence: 99%

“…25% of all proteins may even be completely disordered [135]. Not surprisingly, considering the vast number of presumably disordered proteins, some of these have been implicated in cancer development [138] as well as in neurodegenerative and cardiovascular diseases [140]. As disorder may lead to protein aggregation, a key problem in many neurodegenerative diseases, it was expected that disordered proteins may be subject to tight regulation.…”

Section: Disordered Proteins and Protein Segments Are Crucial For Celmentioning

confidence: 99%

Beyond ‘furballs’ and ‘dumpling soups’ – towards a molecular architecture of signaling complexes and networks

2012

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a b s t r a c tThe molecular architectures of intracellular signaling networks are largely unknown. Understanding their design principles and mechanisms of processing information is essential to grasp the molecular basis of virtually all biological processes. This is particularly challenging for human pathologies like cancers, as essentially each tumor is a unique disease with vastly deranged signaling networks. However, even in normal cells we know almost nothing. A few 'signalosomes', like the COP9 and the TCR signaling complexes have been described, but detailed structural information on their architectures is largely lacking. Similarly, many growth factor receptors, for example EGF receptor, insulin receptor and c-Met, signal via huge protein complexes built on large platform proteins (Gab, Irs/Dok, p130Cas[BCAR1], Frs families etc.), which are structurally not well understood. Subsequent higher order processing events remain even more enigmatic. We discuss here methods that can be employed to study signaling architectures, and the importance of too often neglected features like macromolecular crowding, intrinsic disorder in proteins and the sophisticated cellular infrastructures, which need to be carefully considered in order to develop a more mature understanding of cellular signal processing.

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Intrinsic Disorder and Functional Proteomics

Cited by 654 publications

References 204 publications

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Resilience of death: intrinsic disorder in proteins involved in the programmed cell death

Tunable Membrane Binding of the Intrinsically Disordered Dehydrin Lti30, a Cold-Induced Plant Stress Protein

Beyond ‘furballs’ and ‘dumpling soups’ – towards a molecular architecture of signaling complexes and networks

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