110,433 research outputs found
Metazoans evolved by taking domains from soluble proteins to expand intercellular communication network.
A central question in animal evolution is how multicellular animals evolved from unicellular ancestors. We hypothesize that membrane proteins must be key players in the development of multicellularity because they are well positioned to form the cell-cell contacts and to provide the intercellular communication required for the creation of complex organisms. Here we find that a major mechanism for the necessary increase in membrane protein complexity in the transition from non-metazoan to metazoan life was the new incorporation of domains from soluble proteins. The membrane proteins that have incorporated soluble domains in metazoans are enriched in many of the functions unique to multicellular organisms such as cell-cell adhesion, signaling, immune defense and developmental processes. They also show enhanced protein-protein interaction (PPI) network complexity and centrality, suggesting an important role in the cellular diversification found in complex organisms. Our results expose an evolutionary mechanism that contributed to the development of higher life forms
Allo-network drugs: Extension of the allosteric drug concept to protein-protein interaction and signaling networks
Allosteric drugs are usually more specific and have fewer side effects than orthosteric drugs targeting the same
protein. Here, we overview the current knowledge on allosteric signal transmission from the network point of view, and show that most intra-protein conformational changes may be dynamically transmitted across protein-protein interaction and signaling networks of the cell. Allo-network drugs influence the pharmacological target protein indirectly using specific inter-protein network pathways. We show that allo-network drugs may have a higher efficiency to change the networks of human cells than those of other organisms, and can be designed to have specific effects on cells in a diseased state. Finally, we summarize possible methods to identify allo-network drug targets and sites, which may develop to a promising new area of systems-based drug design
Disordered proteins and network disorder in network descriptions of protein structure, dynamics and function. Hypotheses and a comprehensive review
During the last decade, network approaches became a powerful tool to describe protein structure and dynamics. Here we review the links between disordered proteins and the associated networks, and describe the consequences of local, mesoscopic and global network disorder on changes in protein structure and dynamics. We introduce a new classification of protein networks into ‘cumulus-type’, i.e., those similar to puffy (white) clouds, and ‘stratus-type’, i.e., those similar to flat, dense (dark) low-lying clouds, and relate these network types to protein disorder dynamics and to differences in energy transmission processes. In the first class, there is limited overlap between the modules, which implies higher rigidity of the individual units; there the conformational changes can be described by an ‘energy transfer’ mechanism. In the second class, the topology presents a compact structure with significant overlap between the modules; there the conformational changes can be described by ‘multi-trajectories’; that is, multiple highly populated pathways. We further propose that disordered protein regions evolved to help other protein segments reach ‘rarely visited’ but functionally-related states. We also show the role of disorder in ‘spatial games’ of amino acids; highlight the effects of intrinsically disordered proteins (IDPs) on cellular networks and list some possible studies linking protein disorder and protein structure networks
Uniformly curated signaling pathways reveal tissue-specific cross-talks and support drug target discovery
Motivation: Signaling pathways control a large variety of cellular processes.
However, currently, even within the same database signaling pathways are often
curated at different levels of detail. This makes comparative and cross-talk
analyses difficult. Results: We present SignaLink, a database containing 8
major signaling pathways from Caenorhabditis elegans, Drosophila melanogaster,
and humans. Based on 170 review and approx. 800 research articles, we have
compiled pathways with semi-automatic searches and uniform, well-documented
curation rules. We found that in humans any two of the 8 pathways can
cross-talk. We quantified the possible tissue- and cancer-specific activity of
cross-talks and found pathway-specific expression profiles. In addition, we
identified 327 proteins relevant for drug target discovery. Conclusions: We
provide a novel resource for comparative and cross-talk analyses of signaling
pathways. The identified multi-pathway and tissue-specific cross-talks
contribute to the understanding of the signaling complexity in health and
disease and underscore its importance in network-based drug target selection.
Availability: http://SignaLink.orgComment: 9 pages, 4 figures, 2 tables and a supplementary info with 5 Figures
and 13 Table
Chaperones as integrators of cellular networks: Changes of cellular integrity in stress and diseases
Cellular networks undergo rearrangements during stress and diseases. In
un-stressed state the yeast protein-protein interaction network (interactome)
is highly compact, and the centrally organized modules have a large overlap.
During stress several original modules became more separated, and a number of
novel modules also appear. A few basic functions, such as the proteasome
preserve their central position. However, several functions with high energy
demand, such the cell-cycle regulation loose their original centrality during
stress. A number of key stress-dependent protein complexes, such as the
disaggregation-specific chaperone, Hsp104, gain centrality in the stressed
yeast interactome. Molecular chaperones, heat shock, or stress proteins form
complex interaction networks (the chaperome) with each other and their
partners. Here we show that the human chaperome recovers the segregation of
protein synthesis-coupled and stress-related chaperones observed in yeast
recently. Examination of yeast and human interactomes shows that (1) chaperones
are inter-modular integrators of protein-protein interaction networks, which
(2) often bridge hubs and (3) are favorite candidates for extensive
phosphorylation. Moreover, chaperones (4) become more central in the
organization of the isolated modules of the stressed yeast protein-protein
interaction network, which highlights their importance in the de-coupling and
re-coupling of network modules during and after stress. Chaperone-mediated
evolvability of cellular networks may play a key role in cellular adaptation
during stress and various polygenic and chronic diseases, such as cancer,
diabetes or neurodegeneration.Comment: 13 pages, 3 figures, 1 glossar
Predictive genomics: A cancer hallmark network framework for predicting tumor clinical phenotypes using genome sequencing data
We discuss a cancer hallmark network framework for modelling
genome-sequencing data to predict cancer clonal evolution and associated
clinical phenotypes. Strategies of using this framework in conjunction with
genome sequencing data in an attempt to predict personalized drug targets, drug
resistance, and metastasis for a cancer patient, as well as cancer risks for a
healthy individual are discussed. Accurate prediction of cancer clonal
evolution and clinical phenotypes will have substantial impact on timely
diagnosis, personalized management and prevention of cancer.Comment: 5 figs, related papers, visit lab homepage:
http://www.cancer-systemsbiology.org, Seminar in Cancer Biology, 201
Principles of microRNA regulation of a human cellular signaling network
MicroRNAs (miRNAs) are endogenous 22-nucleotide RNAs, which suppress gene
expression by selectively binding to the 3-noncoding region of specific message
RNAs through base-pairing. Given the diversity and abundance of miRNA targets,
miRNAs appear to functionally interact with various components of many cellular
networks. By analyzing the interactions between miRNAs and a human cellular
signaling network, we found that miRNAs predominantly target positive
regulatory motifs, highly connected scaffolds and most downstream network
components such as signaling transcription factors, but less frequently target
negative regulatory motifs, common components of basic cellular machines and
most upstream network components such as ligands. In addition, when an adaptor
has potential to recruit more downstream components, these components are more
frequently targeted by miRNAs. This work uncovers the principles of miRNA
regulation of signal transduction networks and implies a potential function of
miRNAs for facilitating robust transitions of cellular response to
extracellular signals and maintaining cellular homeostasis
- …