The evolutionary origin of eukaryotic transmembrane signal transduction

1. A comparison was made of transmembrane signal transduction mechanisms in different eukaryotes and prokaryotes. 2. Much attention was given to eukaryotic microbes and their signal transduction mechanisms, since these organisms are intermediate in complexity between animals, plants and bacteria. 3. Signal transduction mechanisms in eukaryotic microbes, however, do not appear to be intermediate between those in animals, plants and bacteria, but show features characteristic of the higher eukaryotes. 4. These similarities include the regulation of receptor function, adenylate cyclase activity, the presence of a phosphatidylinositol cycle and of GTP-binding regulatory proteins. 5. It is proposed that the signal transduction systems known to operate in present-day eukaryotes evolved in the earliest eukaryotic cells.     

The evolution of hormonal signalling systems.

1. A comparative analysis was made of chemosignalling systems responsible for the action of hormones, hormone-like substances, pheromones, etc. in vertebrates--multicellular invertebrates--unicellular eukaryotes. Many common features revealed in structural-functional organization of the above systems give evidence of their evolutionary conservatism. 2. It was shown that some molecular components as well as signal transduction mechanisms similar to those of higher eukaryote hormonal signalling systems are present in such early organisms as bacteria. This allowed a suggestion that the roots of chemosignalling systems are likely to be found in prokaryotes. 3. The evolution of hormonal signalling systems is discussed in terms of current theories of the origin of eukaryotic cell, its organelles and components. A hypothesis is put forward about endosymbiotic genesis of these signal transduction systems in eukaryotes. 4. A possible evolutionary scenario of the formation of hormonocompetent systems is proposed with hormone-sensitive adenylate cyclase complex taken as an example.     

The functions of Ca(2+) in bacteria: a role for EF-hand proteins?

In bacteria, Ca(2+) is implicated in a wide variety of cellular processes, including the cell cycle and cell division. Dedicated influx and efflux systems tightly control the low cytoplasmic Ca(2+) levels in prokaryotes. Additionally, the growing number of proteins containing various Ca(2+)-binding motifs supports the importance of Ca(2+), which controls various protein functions by affecting protein stability, enzymatic activity or signal transduction. The existence of calmodulin-like proteins (containing EF-hand motifs) in bacteria is a long-standing hypothesis. Analysis of the prokaryotic protein sequences available in the databases has revealed the presence of several calmodulin-like proteins containing two or more authentic EF-hand motifs, suggesting that calmodulin-like proteins could be involved in Ca(2+) regulation in bacteria.     

Bacterial signalling involving eukaryotic-type protein kinases

Protein Ser, Thr and Tyr kinases play essential roles in signal transduction in organisms ranging from yeast to mammals, where they regulate a variety of cellular activities. During the last few years, a number of genes that encode eukaryotic-type protein kinases have also been identified in four different bacterial species, suggesting that such enzymes are also widespread in prokaryotes. Although many of them have yet to be fully characterized, several studies indicate that eukaryotic-type protein kinases play important roles in regulating cellular activities of these bacteria, such as cell differentiation, pathogenicity and secondary metabolism. A model based on the possible coupling between two-component systems and eukaryotic-type protein kinases is proposed to explain the function of eukaryotic-type protein kinases in bacterial signalling in the light of studies in bacteria, as well as in plants and yeast. These two groups of eukaryotes possess signal-transduction pathways involving both two-component systems and eukaryotic protein kinases.     

Small molecule-mediated density-dependent control of gene expression in prokaryotes: bioluminescence and the biosynthesis of carbapenem antibiotics.

Sophisticated signal transduction systems enable prokaryotes to sense their growth environment and mount an appropriate adaptive response. Signal transduction and gene regulation through the phosphorylation of two regulatory components is now recognised as one of the major global regulatory networks in bacteria. However, not all types of sensor-regulator circuits relay information via phosphoryl transfer. The Vibrio fischeri LuxR protein which has previously been characterised as a member of the response-regulator superfamily responds to a small diffusible signal molecule N-(3-oxohexanoyl)homoserine lactone (HSL). Biosynthesis of HSL in V. fischeri is dependent on the expression of the luxI gene. Until recently, the role of HSL as an 'autoinducer' was thought to be restricted to V. fischeri and a few related marine bacteria in which it controls the onset of bioluminescence. However, we have discovered that a diverse group of terrestrial bacteria: (1) produce HSL; (2) possess genes analogous to luxI; and (3) exhibit cell density-dependent induction of bioluminesence when transformed with a recombinant plasmid carrying V. fischeri lux genes but lacking luxI. In one of these, Erwinia carotovora, HSL is shown to mediate the cell density-dependent biosynthesis of a carbapenem antibiotic.     

Photoresponsive cAMP signal transduction in cyanobacteria.

The molecular mechanism of cAMP-mediated signal transduction from light reception to the physiological response via regulation of gene expression in cyanobacteria is described based on our recent works. Cyanobacteria are known as the organisms that acquired oxygen-evolving, higher plant type photosynthesis. We have found that the cellular cAMP level in the filamentous cyanobacteria Anabaena was oppositely regulated by red and far-red light, i.e., decreasing and increasing, respectively, suggesting that a phytochrome-like red/far-red photoreversible pigment regulates the activity of a certain adenylate cyclase. On the other hand, in the unicellular cyanobacterium Synechocystis cellular cAMP content was increased by blue light irradiation, which led to stimulation of cell motility. The cAMP signaling pathway is known to play an important role in the regulation of various biological activities by altering enzyme activities or controlling gene expression levels in both prokaryotes and eukaryotes. We have isolated genes for adenylate cyclases and cAMP receptor proteins and characterized their molecular properties. Disruption of these genes resulted in the loss of cell motility. It is concluded that the light signal was transmitted by cAMP signal cascade in cyanobacteria.     

Protein Clusters in Phosphotyrosine Signal Transduction

Signal transduction systems based on tyrosine phosphorylation are central to cell–cell communication in multicellular organisms. Typically, in such a system, the signal is initiated by activating tyrosine kinases associated with transmembrane receptors, which induces tyrosine phosphorylation of the receptor and/or associated proteins. The phosphorylated tyrosines then serve as docking sites for the binding of various downstream effector proteins. It has long been observed that the cooperative association of the receptors and effectors produces higher-order protein assemblies (clusters) following signal activation in virtually all phosphotyrosine signal transduction systems. However, mechanistic studies on how such clustering processes affect signal transduction outcomes have only emerged recently. Here we review current progress in decoding the biophysical consequences of clustering on the behavior of the system, and how clustering affects how these receptors process information.     

Zn(II) metabolism in prokaryotes

It is difficult to over-state the importance of Zn(II) in biology. It is a ubiquitous essential metal ion and plays a role in catalysis, protein structure and perhaps as a signal molecule, in organisms from all three kingdoms. Of necessity, organisms have evolved to optimise the intracellular availability of Zn(II) despite the extracellular milieu. To this end, prokaryotes contain a range of Zn(II) import, Zn(II) export and/or binding proteins, some of which utilise either ATP or the chemiosmotic potential to drive the movement of Zn(II) across the cytosolic membrane, together with proteins that facilitate the diffusion of this ion across either the outer or inner membranes of prokaryotes. This review seeks to give an overview of the systems currently classified as altering Zn(II) availability in prokaryotes.     

真菌双组分信号转导系统及其抑制剂研究进展

双组分信号转导系统存在于包括真菌在内的大部分低等真核生物、原核生物及一些植物中。真菌双组分信号转导蛋白在细胞新陈代谢、毒力以及致病性等方面具有重要作用,且目前在人类细胞中尚未发现双组分信号转导系统。因此,探明真菌双组分信号转导系统的机制,可为抑制剂的设计和寻找提供多个"靶点",从而研制出能够抗致病性真菌而不对宿主细胞造成损伤的新型抗真菌药物。本文就近年来真菌双组分信号转导系统及其潜在抑制剂进行综述。     

Diversity in chemotaxis mechanisms among the bacteria and archaea.

The study of chemotaxis describes the cellular processes that control the movement of organisms toward favorable environments. In bacteria and archaea, motility is controlled by a two-component system involving a histidine kinase that senses the environment and a response regulator, a very common type of signal transduction in prokaryotes. Most insights into the processes involved have come from studies of Escherichia coli over the last three decades. However, in the last 10 years, with the sequencing of many prokaryotic genomes, it has become clear that E. coli represents a streamlined example of bacterial chemotaxis. While general features of excitation remain conserved among bacteria and archaea, specific features, such as adaptational processes and hydrolysis of the intracellular signal CheY-P, are quite diverse. The Bacillus subtilis chemotaxis system is considerably more complex and appears to be similar to the one that existed when the bacteria and archaea separated during evolution, so that understanding this mechanism should provide insight into the variety of mechanisms used today by the broad sweep of chemotactic bacteria and archaea. However, processes even beyond those used in E. coli and B. subtilis have been discovered in other organisms. This review emphasizes those used by B. subtilis and these other organisms but also gives an account of the mechanism in E. coli.     

What are archaebacteria: life's third domain or monoderm prokaryotes related to Gram-positive bacteria? A new proposal for the classification of prokaryotic organisms

The evolutionary relationship within prokaryotes is examined based on signature sequences (defined as conserved inserts or deletions shared by specific taxa) and phylogenies derived from different proteins. Archaebacteria are indicated as being monophyletic by a number of proteins related to the information transfer processes. In contrast, for several other highly conserved proteins, common signature sequences are present in archaebacteria and Gram-positive bacteria, whereas Gram-negative bacteria are indicated as being distinct. For these proteins, archaebacteria do not form a phylogenetically distinct clade but show polyphyletic branching within Gram-positive bacteria. A closer relationship of archaebacteria to Gram-positive bacteria in comparison with Gram-negative bacteria is generally seen for the majority of the available gene/protein sequences. To account for these results and the fact that both archaebacteria and Gram-positive bacteria are prokaryotes surrounded by a single cell membrane, I propose that the primary division within prokaryotes is between monoderm prokaryotes (surrounded by a single membrane) and diderm prokaryotes (i.e. all true Gram-negative bacteria containing both an inner cytoplasmic membrane and an outer membrane). This proposal is consistent with both cell morphology and signature sequences in different proteins. The monophyletic nature of archaebacteria for some genes, and their polyphyletic branching within Gram-positive bacteria as suggested by others, is critically examined, and several explanations, including derivation of archaebacteria from Gram-positive bacteria in response to antibiotic selection pressure, are proposed. Signature sequences in proteins also indicate that the low-G + C Gram-positive bacteria are phylogenetically distinct from the high-G + C Gram-positive group and that the diderm prokaryotes (i.e. Gram-negative bacteria) appear to have evolved from the latter group. Protein phylogenies and signature sequences also show that all eukaryotic cells have received significant gene contributions from both an archaebacterium and a Gram-negative eubacterium. Thus, the hypothesis that archaebacteria and eukaryotes shared a common ancestor exclusive of eubacteria is not supported. These observations provide evidence for an alternate view of the evolutionary relationship among living organisms that is different from the currently popular three-domain proposal.     

Bacterial glycoproteins: functions,biosynthesis and applications

Although widely distributed in eukaryotic cells glycoproteins appear to be rare in prokaryotic organisms. The prevalence of the misconception that bacteria do not glycosylate their proteins has been a subject matter of discussion for a long time. Glycoconjugates that are linked to proteins or peptides, generated by the ribosomal translational mechanism have been reported only in the last two to three decades in a few prokaryotic organisms. Most studied prokaryotic glycoproteins are the S-layer glycoproteins of Archeabacteria. Apart from these, membrane-associated, surface-associated, secreted glycoproteins and exoenzymes glycoproteins are also well documented in both, Archea and Eubacteria. From the recent literature, it is now clear that prokaryotes are capable of glycosylating proteins. In general, prokaryotes are deprived of the cellular organelles required for glycosylation. In prokaryotes many different glycoprotein structures have been observed that display much more variation than that observed in eukaryotes. Besides following similar mechanisms in the process of glycosylation, prokaryotes have also been shown to use mechanisms that are different from those found in eukaryotes. The knowledge pertaining to the functional aspects of prokaryotic glycoproteins is rather scarce. This review summarizes developments and understanding relating to characteristics, synthesis, and functions of prokaryotic glycoproteins. An extensive summary of glycosylation that has been reported to occur in bacteria has also been tabulated. Various possible applications of these diverse biomolecules in biotechnology, vaccine development, pharmaceutics and diagnostics are also touched upon.     

Signal transduction in bacterial chemotaxis

Motile bacteria respond to environmental cues to move to more favorable locations. The components of the chemotaxis signal transduction systems that mediate these responses are highly conserved among prokaryotes including both eubacterial and archael species. The best-studied system is that found in Escherichia coli. Attractant and repellant chemicals are sensed through their interactions with transmembrane chemoreceptor proteins that are localized in multimeric assemblies at one or both cell poles together with a histidine protein kinase, CheA, an SH3-like adaptor protein, CheW, and a phosphoprotein phosphatase, CheZ. These multimeric protein assemblies act to control the level of phosphorylation of a response regulator, CheY, which dictates flagellar motion. Bacterial chemotaxis is one of the most-understood signal transduction systems, and many biochemical and structural details of this system have been elucidated. This is an exciting field of study because the depth of knowledge now allows the detailed molecular mechanisms of transmembrane signaling and signal processing to be investigated.     

Cache Domains That are Homologous to,but Different from PAS Domains Comprise the Largest Superfamily of Extracellular Sensors in Prokaryotes

Cellular receptors usually contain a designated sensory domain that recognizes the signal. Per/Arnt/Sim (PAS) domains are ubiquitous sensors in thousands of species ranging from bacteria to humans. Although PAS domains were described as intracellular sensors, recent structural studies revealed PAS-like domains in extracytoplasmic regions in several transmembrane receptors. However, these structurally defined extracellular PAS-like domains do not match sequence-derived PAS domain models, and thus their distribution across the genomic landscape remains largely unknown. Here we show that structurally defined extracellular PAS-like domains belong to the Cache superfamily, which is homologous to, but distinct from the PAS superfamily. Our newly built computational models enabled identification of Cache domains in tens of thousands of signal transduction proteins including those from important pathogens and model organisms. Furthermore, we show that Cache domains comprise the dominant mode of extracellular sensing in prokaryotes.     

Proposed role of drug-metabolizing enzymes: regulation of steady state levels of the ligands that effect growth, homeostasis, differentiation, and neuroendocrine functions.

Every ligand known to bind to a receptor in the nuclear hormone receptor superfamily is involved in a variety of signal transduction pathways effecting growth, morphogenesis, homeostasis, proliferation, and neuroendocrine functions. Often these ligands are associated with increases in particular subsets of cytochromes P450 and other drug-metabolizing enzymes. Interestingly, certain of these enzymes participate in the metabolism (synthesis as well as degradation) of these ligands. It appears that genes coding for certain drug-metabolizing enzymes might have existed on this planet at least 1 billion years before the presence of plants, animals, and drugs. An early role for oxidative enzymes in prokaryotes most likely involved energy substrate utilization: insertion of oxygen into various inaccessible carbon and other food sources, thereby rendering them accessible to further metabolism. It is proposed that a later development of these "drug-metabolizing enzymes" in prokaryotes and early eukaryotes might be related to their metabolic ability to control the steady state levels of the ligands that modulate cell division, growth, morphogenesis, and mating, and that this role has diversified in numerous additional signal transduction pathways and exists today in all eukaryotes.     

Diversity and distribution of hemerythrin-like proteins in prokaryotes

Hemerythrins are oxygen-binding proteins found in the body fluids and tissues of certain invertebrates. Oxygen is bound at a nonheme iron centre consisting of two oxo-bridged iron atoms bound to a characteristic set of conserved histidine: aspartate and glutamate residues with the motifs H-HxxxE-HxxxH-HxxxxD. It has recently been demonstrated biochemically that two bacterial proteins bearing the same motifs do in fact possess similar iron centres and bind oxygen in the same way. The recent profusion of prokaryotic genomic sequence data has shown that proteins bearing hemerythrin motifs are present in a wide variety of bacteria, and a few archaea. Some of these are short proteins as in eukaryotes; others appear to consist of a hemerythrin domain fused to another domain, generally a putative signal transduction domain such as a methyl-accepting chemotaxis protein, a histidine kinase, or a GGDEF protein (cyclic di-GMP synthase). If, as initial evidence suggests, these are in fact hemerythrin-like oxygen-binding proteins, then their diversity in prokaryotes far exceeds that seen in eukaryotes. Here, a survey is presented of prokaryotic protein sequences bearing hemerythrin-like motifs, for which the designation 'bacteriohemerythrins' is proposed, and their functions are speculated.     

A single calcium flux triggers chromosome replication, segregation and septation in bacteria: a model

Abrupt changes in the concentration of intracellular calcium, through the mediation of calmodulin, is presumed to play an essential role in many molecular processes in eukaryotes including triggering cell cycle events. Although early studies failed to establish any role for calcium in the growth of bacteria, recent studies have demonstrated that bacteria have several calcium transport systems, and an intracellular concentration of free calcium identical to that of higher organisms, which appears to fluctuate during the cell cycle. Moreover, calmodulin-like proteins have been reported in bacteria, and the growth of E. coli is sensitive to calmodulin inhibitors. In this article we propose that a single flux of calcium, abruptly raising the intracellular concentration of free calcium, is responsible for the triggering in bacteria of the major cell cycle events, initiation of DNA replication, chromosome partition and cell division. We predict that major roles in this process will involve a bacterial calmodulin-like protein and a primitive cytoskeleton. The mechanism of triggering different cell cycle events by a single calcium flux is discussed.