Spatial organization enhances versatility and specificity in cyclic di-GMP signaling

2020 ◽  
Vol 401 (12) ◽  
pp. 1323-1334
Author(s):  
Sandra Kunz ◽  
Peter L. Graumann
Keyword(s):  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Spatial Organization ◽  
Caulobacter Crescentus ◽  
Second Messenger ◽  
Protein Protein Interactions ◽  
Spatial Cues ◽  
Signaling Specificity ◽  
Regulatory Circuits ◽  
Second Messenger Signaling

AbstractThe second messenger cyclic di-GMP regulates a variety of processes in bacteria, many of which are centered around the decision whether to adopt a sessile or a motile life style. Regulatory circuits include pathogenicity, biofilm formation, and motility in a wide variety of bacteria, and play a key role in cell cycle progression in Caulobacter crescentus. Interestingly, multiple, seemingly independent c-di-GMP pathways have been found in several species, where deletions of individual c-di-GMP synthetases (DGCs) or hydrolases (PDEs) have resulted in distinct phenotypes that would not be expected based on a freely diffusible second messenger. Several recent studies have shown that individual signaling nodes exist, and additionally, that protein/protein interactions between DGCs, PDEs and c-di-GMP receptors play an important role in signaling specificity. Additionally, subcellular clustering has been shown to be employed by bacteria to likely generate local signaling of second messenger, and/or to increase signaling specificity. This review highlights recent findings that reveal how bacteria employ spatial cues to increase the versatility of second messenger signaling.

scholarly journals Targeting Protein-Protein Interactions in the DNA Damage Response Pathways for Cancer Chemotherapy

2021 ◽  
Author(s):  
Kerry Silva McPherson ◽  
Dmitry Korzhnev
Keyword(s):  
Dna Damage ◽  
Dna Damage Response ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Damage Recognition ◽  
Damage Response ◽  
Cellular Dna ◽  
Dna Damage Recognition

Cellular DNA damage response (DDR) is an extensive signaling network that orchestrates DNA damage recognition, repair and avoidance, cell cycle progression and cell death. DDR alternation is a hallmark of...

scholarly journals Schistosoma mansoni polo-like kinases and their function in control of mitosis and parasite reproduction

2011 ◽  
Vol 83 (2) ◽  
pp. 627-635 ◽  
Author(s):  
Colette Dissous ◽  
Christoph G Grevelding ◽  
Thavy Long
Keyword(s):  
Cell Cycle ◽  
Schistosoma Mansoni ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Gonad Development ◽  
Cancer Drug ◽  
Protein Protein Interactions ◽  
Centriole Duplication ◽  
Regulation Of Cell Cycle ◽  
Functional Analyses

Polo-like kinases are important regulators of cell cycle progression and mitosis. They constitute a family of conserved serine/threonine kinases which are highly related in their catalytic domains and contain polo boxes involved in protein-protein interactions and subcellular localization. In mammals, five Plks (Plk 1-5) encompass diverse roles in centrosome dynamics, spindle formation, intra S-phase and G2/M checkpoints and DNA damage response. Plk1 is a key positive regulator of mitosis and is overexpressed in various types of cancers. Plk4 is a divergent member of the Plk family, with essential functions in centriole duplication. Homozygous disruption of Plk1 or Plk4 in mice is lethal in embryos. Two Plk members SmPlk1 and SmSak, homologous to Plk1 and Plk4 respectively, are present in the parasitic platyhelminth Schistosoma mansoni. Structural and functional analyses of SmPlk1 have demonstrated its conserved function in the regulation of cell cycle G2/M transition in Xenopus oocytes. The anti-cancer drug BI 2536 (the most potent and selective Plk1 inhibitor) inhibits specifically the catalytic activity of SmPlk1 and induced profound alterations in schistosome gonads, indicating a role of SmPlk1 in parasite gametogenesis and its potential as a novel chemotherapeutic target against schistosomiasis. Functions of SmSak in cell cycle regulation and schistosome gonad development are currently investigated

scholarly journals The 14-3-3 Proteins as Important Allosteric Regulators of Protein Kinases

2020 ◽  
Vol 21 (22) ◽  
pp. 8824
Author(s):  
Veronika Obsilova ◽  
Tomas Obsil
Keyword(s):  
Protein Interactions ◽  
Cell Cycle Progression ◽  
State Of The Art ◽  
Review Article ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
Kinase Regulation ◽  
Functional Consequences ◽  
Allosteric Regulators ◽  
Structural Aspects

Phosphorylation by kinases governs many key cellular and extracellular processes, such as transcription, cell cycle progression, differentiation, secretion and apoptosis. Unsurprisingly, tight and precise kinase regulation is a prerequisite for normal cell functioning, whereas kinase dysregulation often leads to disease. Moreover, the functions of many kinases are regulated through protein–protein interactions, which in turn are mediated by phosphorylated motifs and often involve associations with the scaffolding and chaperon protein 14-3-3. Therefore, the aim of this review article is to provide an overview of the state of the art on 14-3-3-mediated kinase regulation, focusing on the most recent mechanistic insights into these important protein–protein interactions and discussing in detail both their structural aspects and functional consequences.

scholarly journals Sequence conservation, domain architectures, and phylogenetic distribution of the HD-GYP type c-di-GMP phosphodiesterases

2021 ◽  
Author(s):  
Michael Y. Galperin ◽  
Shan-Ho Chou
Keyword(s):  
Protein Interactions ◽  
Regulatory Protein ◽  
Second Messenger ◽  
Distribution Patterns ◽  
Distribution Functions ◽  
Amino Acid Residues ◽  
Sequence Motifs ◽  
Protein Protein Interactions ◽  
Conserved Sequence ◽  
Common Domain

The HD-GYP domain, named after two of its conserved sequence motifs, was first described in 1999 as a specialized version of the widespread HD phosphohydrolase domain that had additional highly conserved amino acid residues. Domain associations of HD-GYP indicated its involvement in bacterial signal transduction and distribution patterns of this domain suggested that it could serve as a hydrolase of the bacterial second messenger c-di-GMP, in addition to or instead of the EAL domain. Subsequent studies confirmed the ability of various HD-GYP domains to hydrolyze c-di-GMP to linear pGpG and/or GMP. Certain HD-GYP-containing proteins hydrolyze another second messenger, cGAMP, and some HD-GYP domains participate in regulatory protein-protein interactions. The recently solved structures of HD-GYP domains from four distinct organisms clarified the mechanisms of c-di-GMP binding and metal-assisted hydrolysis. However, the HD-GYP domain is poorly represented in public domain databases, which causes certain confusion about its phylogenic distribution, functions, and domain architectures. Here, we present a refined sequence model for the HD-GYP domain and describe the roles of its most conserved residues in metal and/or substrate binding. We also calculate the numbers of HD-GYPs encoded in various genomes and list the most common domain combinations involving HD-GYP, such as the RpfG (REC-HD-GYP), Bd1817 (DUF3391-HD-GYP), and PmGH (GAF-HD-GYP) protein families. We also provide the descriptions of six HD-GYP-associated domains, including four novel integral membrane sensor domains. This work is expected to stimulate studies of diverse HD-GYP-containing proteins, their N-terminal sensor domains, and the signals to which they respond.

scholarly journals The social network of PELP1 and its implications in breast and prostate cancers

2014 ◽  
Vol 21 (4) ◽  
pp. T79-T86 ◽  
Author(s):  
Vijay K Gonugunta ◽  
Lu Miao ◽  
Gangadhara R Sareddy ◽  
Preethi Ravindranathan ◽  
Ratna Vadlamudi ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Interactions ◽  
Ribosome Biogenesis ◽  
Cell Cycle Progression ◽  
Steroid Receptors ◽  
Prognostic Significance ◽  
Protein Protein Interactions ◽  
Cycle Progression ◽  
The Social ◽  
Prostate Cancers

Proline, glutamic acid- and leucine-rich protein 1 (PELP1) is a multi-domain scaffold protein that serves as a platform for various protein–protein interactions between steroid receptors (SRs) and signaling factors and cell cycle, transcriptional, cytoskeletal, and epigenetic remodelers. PELP1 is known to be a coregulator of transcription and participates in the nuclear and extranuclear functions of SRs, ribosome biogenesis, and cell cycle progression. The expression and localization of PELP1 are dysregulated in hormonal cancers including breast and prostate cancers. This review focuses on the interactive functions and therapeutic and prognostic significance of PELP1 in breast and prostate cancers.

scholarly journals Contribution of Physical Interactions to Signaling Specificity between a Diguanylate Cyclase and Its Effector

mBio ◽  
2015 ◽  
Vol 6 (6) ◽  
Author(s):  
Kurt M. Dahlstrom ◽  
Krista M. Giglio ◽  
Alan J. Collins ◽  
Holger Sondermann ◽  
George A. O’Toole
Keyword(s):  
Protein Interactions ◽  
Second Messenger ◽  
Target Protein ◽  
Physical Interaction ◽  
Content Type ◽  
Signaling Specificity ◽  
Cellular Processes ◽  
Diguanylate Cyclases ◽  
Cellular Behaviors ◽  
Physical Interactions

ABSTRACT Cyclic diguanylate (c-di-GMP) is a bacterial second messenger that controls multiple cellular processes. c-di-GMP networks have up to dozens of diguanylate cyclases (DGCs) that synthesize c-di-GMP along with many c-di-GMP-responsive target proteins that can bind and respond to this signal. For such networks to have order, a mechanism(s) likely exists that allow DGCs to specifically signal their targets, and it has been suggested that physical interactions might provide such specificity. Our results show a DGC from Pseudomonas fluorescens physically interacting with its target protein at a conserved interface, and this interface can be predictive of DGC-target protein interactions. Furthermore, we demonstrate that physical interaction is necessary for the DGC to maximally signal its target. If such “local signaling” is a theme for even a fraction of the DGCs used by bacteria, it becomes possible to posit a model whereby physical interaction allows a DGC to directly signal its target protein, which in turn may help curtail undesired cross talk with other members of the network. IMPORTANCE An important question in microbiology is how bacteria make decisions using a signaling network made up of proteins that make, break, and bind the second messenger c-di-GMP, which is responsible for controlling many cellular behaviors. Previous work has shown that a given DGC enzyme will signal for specific cellular outputs, despite making the same diffusible molecule as its sibling DGCs in the unpartitioned space of the bacterial cell. Understanding how one DGC differentiates its output from the dozens of other such enzymes in the cell is synonymous with understanding a large component of the bacterial decision-making machinery. We present evidence for a helix on a DGC used to physically associate with its target protein, which is necessary to achieve maximal signaling.

scholarly journals CELL SYSTEMS BIOLOGY OF TRANSLATION FACTORS AND PROTEASOME-TARGETED PROTEIN COMPLEXES ASSOCIATED WITH AGC KINASE SCH9

2020 ◽  
Author(s):  
Alex Sobko
Keyword(s):  
Protein Synthesis ◽  
Protein Kinase ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Protein Complexes ◽  
Translation Initiation Factor ◽  
Initiation Factor ◽  
Protein Protein Interactions ◽  
Functional Connections ◽  
Translation Factors

Sch9 appears to be the Saccharomyces cerevisiae homolog of protein kinase B and S6 kinase and is involved in the control of numerous nutrient-sensitive processes, including regulation of cell size, cell cycle progression, and stress resistance. Sch9 has also been implicated in the regulation of replicative and chronological life span. The availability of data from global studies of protein-protein interactions now makes it possible to predict and validate functional connections between Sch9, its putative substrates, and other proteins. Sch9 appears to be involved in control of biosynthetic and catabolic pathways. Thus, the analysis of Sch9-associated proteins indicates that this kinase may be involved in regulation of protein synthesis. Sch9 forms a complex with, and, presumably, phosphorylates starvation- and stress-induced protein kinase GCN2, which, in turn, phosphorylates translation initiation factor eIF2alpha. Sch9 also interacts with translation factors Arc1, Pab1 and prion-like protein Sup35. Thus, Sch9 may be part of the mechanism that relays availability of nutrients to utilization of glucose and to the rates of protein synthesis. One of the interesting outcomes of the proteome-wide analysis of protein-protein interactions in yeast is the finding that Sch9 associates with Shp1, Cdc48, and Ufd1, which form a complex responsible for the recognition and targeting of ubiquitinated proteins to the proteasome for degradation. It is unknown and remains to be elucidated, whether mammalian homologues of Sch9 are also associated with the proteins involved in translation/protein synthesis and proteasomal degradation.

scholarly journals An extensive program of periodic alternative splicing linked to cell cycle progression

eLife ◽  
2016 ◽  
Vol 5 ◽  
Author(s):  
Daniel Dominguez ◽  
Yi-Hsuan Tsai ◽  
Robert Weatheritt ◽  
Yang Wang ◽  
Benjamin J Blencowe ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Alternative Splicing ◽  
Protein Interactions ◽  
Cell Cycle Progression ◽  
Cell Cycle Control ◽  
Mitotic Cell ◽  
Protein Protein Interactions ◽  
Post Translational Modification ◽  
Sr Protein ◽  
Cycle Dependent

Progression through the mitotic cell cycle requires periodic regulation of gene function at the levels of transcription, translation, protein-protein interactions, post-translational modification and degradation. However, the role of alternative splicing (AS) in the temporal control of cell cycle is not well understood. By sequencing the human transcriptome through two continuous cell cycles, we identify ~1300 genes with cell cycle-dependent AS changes. These genes are significantly enriched in functions linked to cell cycle control, yet they do not significantly overlap genes subject to periodic changes in steady-state transcript levels. Many of the periodically spliced genes are controlled by the SR protein kinase CLK1, whose level undergoes cell cycle-dependent fluctuations via an auto-inhibitory circuit. Disruption of CLK1 causes pleiotropic cell cycle defects and loss of proliferation, whereas CLK1 over-expression is associated with various cancers. These results thus reveal a large program of CLK1-regulated periodic AS intimately associated with cell cycle control.

scholarly journals Building synthetic cellular organization

2013 ◽  
Vol 24 (23) ◽  
pp. 3585-3587 ◽  
Author(s):  
Jessica K. Polka ◽  
Pamela A. Silver
Keyword(s):  
Synthetic Biology ◽  
Protein Interactions ◽  
Cell Biology ◽  
Spatial Organization ◽  
Biological Significance ◽  
Cellular Organization ◽  
Protein Protein Interactions

The elaborate spatial organization of cells enhances, restricts, and regulates protein–protein interactions. However, the biological significance of this organization has been difficult to study without ways of directly perturbing it. We highlight synthetic biology tools for engineering novel cellular organization, describing how they have been, and can be, used to advance cell biology.

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