Biomolecular Concepts[JOURNAL]
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200 papers
Differential hemoglobin A sequestration between hemodialysis modalities.
Naseeb U, Zarina S, Jägerbrink T … +3 more , Shafqat J, Jörnvall H, Axelsson J
Biomol Concepts · 2017 May · PMID 28422703 · Publisher ↗
This report evaluates plasma protein patterns, dialysates and protein analysis of used dialysis membranes from the same patient under hemodialysis in three separate modalities, using high-flux membranes in concentration-...
This report evaluates plasma protein patterns, dialysates and protein analysis of used dialysis membranes from the same patient under hemodialysis in three separate modalities, using high-flux membranes in concentration-driven transport (HD), convection-driven hemofiltration (HF) and combined hemodialfiltration (HDF). The plasma protein changes induced by each of the three dialysis modalities showed small differences in proteins identified towards our previous plasma analyses of chronic kidney disease (CKD) patients. The used dialysate peptide concentrations likewise exhibited small differences among the modalities and varied in the same relative order as the plasma changes, with protein losses in the order HD>HDF>HF. The membrane protein deposits allowed quantification of the relative Hb removal ratios as ~1.7 for HD and ~1.2 for HDF vs. ~1.0 for HF. Hence, plasma protein alterations, dialysate peptide contents and membrane Hb deposits all identify HD as the modality with the most extensive filtration results and exemplifies the accessibility of protein analysis of used membrane filters for evaluation of dialysis efficiencies.
SUMO conjugation - a mechanistic view.
Pichler A, Fatouros C, Lee H … +1 more , Eisenhardt N
Biomol Concepts · 2017 Mar · PMID 28284030 · Publisher ↗
The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities...
The regulation of protein fate by modification with the small ubiquitin-related modifier (SUMO) plays an essential and crucial role in most cellular pathways. Sumoylation is highly dynamic due to the opposing activities of SUMO conjugation and SUMO deconjugation. SUMO conjugation is performed by the hierarchical action of E1, E2 and E3 enzymes, while its deconjugation involves SUMO-specific proteases. In this review, we summarize and compare the mechanistic principles of how SUMO gets conjugated to its substrate. We focus on the interplay of the E1, E2 and E3 enzymes and discuss how specificity could be achieved given the limited number of conjugating enzymes and the thousands of substrates.
Alzheimer's disease as an inflammatory disease.
Bolós M, Perea JR, Avila J
Biomol Concepts · 2017 Mar · PMID 28231054 · Publisher ↗
Alzheimer's disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leadi...
Alzheimer's disease (AD) is a neurodegenerative condition characterized by the formation of amyloid-β plaques, aggregated and hyperphosphorylated tau protein, activated microglia and neuronal cell death, ultimately leading to progressive dementia. In this short review, we focus on neuroinflammation in AD. Specifically, we describe the participation of microglia, as well as other factors that may contribute to inflammation, in neurodegeneration.
Optical tweezers studies of transcription by eukaryotic RNA polymerases.
Lisica A, Grill SW
Biomol Concepts · 2017 Mar · PMID 28222010 · Publisher ↗
Transcription is the first step in the expression of genetic information and it is carried out by large macromolecular enzymes called RNA polymerases. Transcription has been studied for many years and with a myriad of ex...
Transcription is the first step in the expression of genetic information and it is carried out by large macromolecular enzymes called RNA polymerases. Transcription has been studied for many years and with a myriad of experimental techniques, ranging from bulk studies to high-resolution transcript sequencing. In this review, we emphasise the advantages of using single-molecule techniques, particularly optical tweezers, to study transcription dynamics. We give an overview of the latest results in the single-molecule transcription field, focusing on transcription by eukaryotic RNA polymerases. Finally, we evaluate recent quantitative models that describe the biophysics of RNA polymerase translocation and backtracking dynamics.
Alzheimer's and Danish dementia peptides induce cataract and perturb retinal architecture in rats.
Reddy GB, Reddy PY, Surolia A
Biomol Concepts · 2017 Mar · PMID 28222009 · Publisher ↗
Familial Danish dementias (FDDs) are autosomal dominant neurodegenerative disorders that are associated with visual defects. In some aspects, FDD is similar to Alzheimer's disease (AD)- the amyloid deposits in FDD and AD...
Familial Danish dementias (FDDs) are autosomal dominant neurodegenerative disorders that are associated with visual defects. In some aspects, FDD is similar to Alzheimer's disease (AD)- the amyloid deposits in FDD and AD are made of short peptides: amyloid β (Aβ) in AD and ADan in FDD. Previously, we demonstrated an interaction between the dementia peptides and α-crystallin leading to lens opacification in organ culture due to impaired chaperone activity of α-crystallin. Herein, we report the in vivo effects of ADan and Aβ on the eye. ADan [reduced (ADan-red) and oxidized (ADan-oxi)] and Aβ (Aβ1-40 and Aβ1-42) were injected intravitreally in rats. The onset of cataract was seen after injection of all the peptides, but the cataract matured by 2 weeks in the case of ADan-red, 5 weeks for ADan-oxi and 6 weeks for Aβ1-40, while Aβ1-42 had minimal effect on cataract progression. The severity of cataract is associated with insolubilization and alterations in crystallins and loss of chaperone activity of α-crystallin. Further, disruption of the architecture of the retina was evident from a loss of rhodopsin, increased gliosis, and the thinning of the retina. These results provide a basis for the dominant heredo-otoophthalmo-encephalopathy (HOOE)/FDD syndrome and indicate that ADan peptides are more potent than Aβpeptides in inflicting visual impairment.
Interleukin-33 plasma levels in patients with relapsing-remitting multiple sclerosis.
Alsahebfosoul F, Rahimmanesh I, Shajarian M … +4 more , Etemadifar M, Sedaghat N, Hejazi Z, Naderi S
Biomol Concepts · 2017 Mar · PMID 28107165 · Publisher ↗
Cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS). Interleukin (IL)-33, one of the recently discovered members of the IL-1 superfamily, is a dual functional cytokine involved in various autoim...
Cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS). Interleukin (IL)-33, one of the recently discovered members of the IL-1 superfamily, is a dual functional cytokine involved in various autoimmune disorders. In a case-control study, venous blood was collected from healthy subjects categorized as control group (n=44) and MS patients (n=44). All recruited patients were clinically diagnosed with relapsing-remitting MS (RRMS), including patients without treatment (new identified cases, n=16) and those treated with interferon beta (IFN-β) (n=28). The plasma levels of IL-33 in subjects were measured with ELISA. Significantly elevated IL-33 plasma levels were observed in RRMS patients (p=0.005). Furthermore, IFN-β-treated MS patients had lower levels of IL-33 compared to the untreated patients (p<0.001). Increased IL-33 plasma levels in the patient group might be associated with development of MS. These results could contribute to our better understanding about the role of IL-33 in the immunopathogenesis of MS.
Unusual structures of CCTG repeats and their participation in repeat expansion.
Guo P, Lam SL
Biomol Concepts · 2016 Dec · PMID 27879482 · Publisher ↗
CCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instab...
CCTG repeat expansion in intron 1 of the cellular nucleic acid-binding protein (CNBP) gene has been identified to be the genetic cause of myotonic dystrophy type 2 (DM2). Yet the underlying reasons for the genetic instability in CCTG repeats remain elusive. In recent years, CCTG repeats have been found to form various types of unusual secondary structures including mini-dumbbell (MDB), hairpin and dumbbell, revealing that there is a high structural diversity in CCTG repeats intrinsically. Upon strand slippage, the formation of unusual structures in the nascent strand during DNA replication has been proposed to be the culprit of CCTG repeat expansions. On the one hand, the thermodynamic stability, size, and conformational dynamics of these unusual structures affect the propensity of strand slippage. On the other hand, these structural properties determine whether the unusual structure can successfully escape from DNA repair. In this short overview, we first summarize the recent advances in elucidating the solution structures of CCTG repeats. We then discuss the potential pathways by which these unusual structures bring about variable sizes of repeat expansion, high strand slippage propensity and efficient repair escape.
Role of non-motile microtubule-associated proteins in virus trafficking.
Portilho DM, Persson R, Arhel N
Biomol Concepts · 2016 Dec · PMID 27879481 · Publisher ↗
Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mec...
Viruses are entirely dependent on their ability to infect a host cell in order to replicate. To reach their site of replication as rapidly and efficiently as possible following cell entry, many have evolved elaborate mechanisms to hijack the cellular transport machinery to propel themselves across the cytoplasm. Long-range movements have been shown to involve motor proteins along microtubules (MTs) and direct interactions between viral proteins and dynein and/or kinesin motors have been well described. Although less well-characterized, it is also becoming increasingly clear that non-motile microtubule-associated proteins (MAPs), including structural MAPs of the MAP1 and MAP2 families, and microtubule plus-end tracking proteins (+TIPs), can also promote viral trafficking in infected cells, by mediating interaction of viruses with filaments and/or motor proteins, and modulating filament stability. Here we review our current knowledge on non-motile MAPs, their role in the regulation of cytoskeletal dynamics and in viral trafficking during the early steps of infection.
Coupling de novo protein folding with subunit exchange into pre-formed oligomeric protein complexes: the 'heritable template' hypothesis.
McMurray MA
Biomol Concepts · 2016 Dec · PMID 27875316 · Publisher ↗
Despite remarkable advances in synthetic biology, the fact remains that it takes a living cell to make a new living cell. The information encoded in the genome is necessary to direct assembly of all cellular components,...
Despite remarkable advances in synthetic biology, the fact remains that it takes a living cell to make a new living cell. The information encoded in the genome is necessary to direct assembly of all cellular components, but it may not be sufficient. Some components (e.g. mitochondria) cannot be synthesized de novo, and instead require pre-existing templates, creating a fundamental continuity of life: if the template information is ever lost, the genomic code cannot suffice to ensure proper biogenesis. One type of information only incompletely encoded in the genome is the structures of macromolecular assemblies, which emerge from the conformations of the constituent molecules coupled with the ways in which these molecules interact. For many, if not most proteins, gene sequence is not the sole determinant of native conformation, particularly in the crowded cellular milieu. A partial solution to this problem lies in the functions of molecular chaperones, encoded by nearly all cellular genomes. Chaperones effectively restrict the ensemble of conformations sampled by polypeptides, promoting the acquisition of native, functional forms, but multiple proteins have evolved ways to achieve chaperone independence, perhaps by coupling folding with higher-order assembly. Here, I propose the existence of another solution: a novel mechanism of de novo folding in which the folding of specific proteins is templated by pre-folded molecules of a partner protein whose own folding also required similar templating. This hypothesis challenges prevailing paradigms by predicting that, in order to achieve a functional fold, some non-prion proteins require a seed passed down through generations.
The microRNA-200 family: still much to discover.
Senfter D, Madlener S, Krupitza G … +1 more , Mader RM
Biomol Concepts · 2016 Dec · PMID 27837593 · Publisher ↗
In the last decade, microRNAs (miRs or miRNAs) became of great interest in cancer research due to their multifunctional and active regulation in a variety of vital cellular processes. In this review, we discuss the miR-2...
In the last decade, microRNAs (miRs or miRNAs) became of great interest in cancer research due to their multifunctional and active regulation in a variety of vital cellular processes. In this review, we discuss the miR-200 family, which is composed of five members (miR-141, miR-200a/200b/200c and miR-429). Although being among the best investigated miRNAs in the field, there are still many open issues. Here, we describe the potential role of miR-200 as prognostic and/or predictive biomarker, its influence on motility and cell migration as well as its role in epithelial to mesenchymal transition (EMT) and metastasis formation in different tumour types. Recent studies also demonstrated the influence of miR-200 on drug resistance and described a correlation between miR-200 expression levels and overall survival of patients. Despite intense research in this field, the full role of the miR-200 family in cancer progression and metastasis is not completely understood and seems to differ between different tumour types and different cellular backgrounds. To elucidate these differences further, a finer characterisation of the role of the individual miRNA-200 family members is currently under investigation.
Advanced glycation end products mediated cellular and molecular events in the pathology of diabetic nephropathy.
Kumar Pasupulati A, Chitra PS, Reddy GB
Biomol Concepts · 2016 Dec · PMID 27816946 · Publisher ↗
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, wide...
Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients and a leading cause of end-stage renal disease (ESRD). Degenerative changes such as glomerular hypertrophy, hyperfiltration, widening of basement membranes, tubulointerstitial fibrosis, glomerulosclerosis and podocytopathy manifest in various degrees of proteinuria in DN. One of the key mechanisms implicated in the pathogenesis of DN is non-enzymatic glycation (NEG). NEG is the irreversible attachment of reducing sugars onto free amino groups of proteins by a series of events, which include the formation of Schiff's base and an Amadori product to yield advanced glycation end products (AGEs). AGE modification of client proteins from the extracellular matrix induces crosslinking, which is often associated with thickening of the basement membrane. AGEs activate several intracellular signaling cascades upon interaction with receptor for AGEs (RAGE), which manifest in aberrant cellular responses such as inflammation, apoptosis and autophagy, whereas other receptors such as AGE-R1, AGE-R3 and scavenger receptors also bind to AGEs and ensue endocytosis and degradation of AGEs. Elevated levels of both serum and tissue AGEs are associated with adverse renal outcome. Increased evidence supports that attenuation of AGE formation and/or inhibition of RAGE activation manifest(s) in improving renal function. This review provides insights of NEG, discusses the cellular and molecular events triggered by AGEs, which manifest in the pathogenesis of DN including renal fibrosis, podocyte epithelial-mesenchymal transition and activation of renin-angiotensin system. Therapies designed to target AGEs, such as inhibitors of AGEs formation and crosslink breakers, are discussed.
Matrix metalloproteinases: an emerging role in regulation of actin microfilament system.
Bildyug N
Biomol Concepts · 2016 Dec · PMID 27763882 · Publisher ↗
Matrix metalloproteinases (MMPs) are implicated in many physiological and pathological processes, including contraction, migration, differentiation, and proliferation. These processes all involve cell phenotype changes,...
Matrix metalloproteinases (MMPs) are implicated in many physiological and pathological processes, including contraction, migration, differentiation, and proliferation. These processes all involve cell phenotype changes, known to be accompanied by reorganization of actin cytoskeleton. Growing evidence indicates a correlation between MMP activity and the dynamics of actin system, suggesting their mutual regulation. Here, data on the influence of MMPs on the actin microfilament system, on the one hand, and the dependence of MMP expression and activation on the organization of actin structures, on the other hand, are reviewed. The different mechanisms of putative actin-MMP regulation are discussed.
MicroRNAs in large herpesvirus DNA genomes: recent advances.
Sorel O, Dewals BG
Biomol Concepts · 2016 Aug · PMID 27544723 · Publisher ↗
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that regulate gene expression. They alter mRNA translation through base-pair complementarity, leading to regulation of genes during both physiological and pathologica...
MicroRNAs (miRNAs) are small non-coding RNAs (ncRNAs) that regulate gene expression. They alter mRNA translation through base-pair complementarity, leading to regulation of genes during both physiological and pathological processes. Viruses have evolved mechanisms to take advantage of the host cells to multiply and/or persist over the lifetime of the host. Herpesviridae are a large family of double-stranded DNA viruses that are associated with a number of important diseases, including lymphoproliferative diseases. Herpesviruses establish lifelong latent infections through modulation of the interface between the virus and its host. A number of reports have identified miRNAs in a very large number of human and animal herpesviruses suggesting that these short non-coding transcripts could play essential roles in herpesvirus biology. This review will specifically focus on the recent advances on the functions of herpesvirus miRNAs in infection and pathogenesis.
The proteasome and epigenetics: zooming in on histone modifications.
Bach SV, Hegde AN
Biomol Concepts · 2016 Aug · PMID 27522625 · Publisher ↗
The proteasome is a structural complex of many proteins that degrades substrates marked by covalent linkage to ubiquitin. Many years of research has shown a role for ubiquitin-proteasome-mediated proteolysis in synaptic...
The proteasome is a structural complex of many proteins that degrades substrates marked by covalent linkage to ubiquitin. Many years of research has shown a role for ubiquitin-proteasome-mediated proteolysis in synaptic plasticity and memory mainly in degrading synaptic, cytoplasmic and nuclear proteins. Recent work indicates that the proteasome has wider proteolytic and non-proteolytic roles in processes such as histone modifications that affect synaptic plasticity and memory. In this review, we assess the evidence gathered from neuronal as well as non-neuronal cell types regarding the function of the proteasome in positive or negative regulation of posttranslational modifications of histones, such as acetylation, methylation and ubiquitination. We discuss the critical roles of the proteasome in clearing excess histone proteins in various cellular contexts and the possible non-proteolytic functions in regulating transcription of target genes. In addition, we summarize the current literature on diverse chromatin-remodeling machineries, such as histone acetyltransferases, deacetylates, methyltransferases and demethylases, as targets for proteasomal degradation across experimental models. Lastly, we provide a perspective on how proteasomal regulation of histone modifications may modulate synaptic plasticity in the nervous system.
Bcl-2 family proteins: master regulators of cell survival.
Hatok J, Racay P
Biomol Concepts · 2016 Aug · PMID 27505095 · Publisher ↗
The most prominent function of proteins of the Bcl-2 family is regulation of the initiation of intrinsic (mitochondrial) pathways of apoptosis. However, recent research has revealed that in addition to regulation of mito...
The most prominent function of proteins of the Bcl-2 family is regulation of the initiation of intrinsic (mitochondrial) pathways of apoptosis. However, recent research has revealed that in addition to regulation of mitochondrial apoptosis, proteins of the Bcl-2 family play important roles in regulating other cellular pathways with a strong impact on cell survival like autophagy, endoplasmic reticulum (ER) stress response, intracellular calcium dynamics, cell cycle progression, mitochondrial dynamics and energy metabolism. This review summarizes the recent knowledge about functions of Bcl-2 family proteins that are related to cell survival.
Alzheimer's disease: presence and role of microRNAs.
Basavaraju M, de Lencastre A
Biomol Concepts · 2016 Aug · PMID 27505094 · Full text
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia. AD affects more than 25 million people globally and is predicted to affect nearly one in 85 people worldw...
Alzheimer's disease (AD) is a progressive neurodegenerative disorder that accounts for the most cases of dementia. AD affects more than 25 million people globally and is predicted to affect nearly one in 85 people worldwide by 2050. AD is characterized by the accumulation of dense plaques of β-amyloid peptide (Aβ) and neurofibrillary tangles of hyperphosphorylated tau that cause impairment in memory, cognition, and daily activities. Although early-onset AD has been linked to several mutations, reliable genetic markers for late-onset AD are lacking. Further, the diagnosis of AD biomarkers has its limitations and cannot detect early-stage AD. The identification of accurate, early, and non-invasive biomarkers for AD is, therefore, an unmet challenge. Recently, microRNAs (miRNAs) have emerged as a novel class of gene regulatory elements with conserved roles in development and disease. Recent discoveries have uncovered roles of miRNAs in several model organisms during aging and have identified potential miRNAs biomarkers of AD. Here we will discuss this emerging field of miRNAs associated with AD and prospects for the future.
Can irisin be a linker between physical activity and brain function?
Zhang J, Zhang W
Biomol Concepts · 2016 Aug · PMID 27356237 · Publisher ↗
Irisin was initially discovered as a novel hormone-like myokine released from skeletal muscle during exercise to improve obesity and glucose dysfunction by stimulating the browning of white adipose tissue. Emerging evide...
Irisin was initially discovered as a novel hormone-like myokine released from skeletal muscle during exercise to improve obesity and glucose dysfunction by stimulating the browning of white adipose tissue. Emerging evidence have indicated that irisin also affects brain function. FNDC5 mRNA and FNDC5/irisin immunoreactivity are present in various regions of the brain. Central irisin is involved in the regulation of neural differentiation and proliferation, neurobehavior, energy expenditure and cardiac function. Elevation of peripheral irisin level stimulates hippocampal genes related to neuroprotection, learning and memory. In this brief review, we summarize the current understanding on neuronal functions of irisin. In addition, we discuss the pros and cons for this molecule as a potential messenger mediating the crosstalk between skeletal muscle and central nervous system during exercise.
High-throughput sequencing offers new insights into 5-hydroxymethylcytosine.
Pang AP, Sugai C, Maunakea AK
Biomol Concepts · 2016 Jun · PMID 27356236 · Full text
Chemical modifications of DNA comprise epigenetic mechanisms that contribute to the maintenance of cellular activities and memory. Although the function of 5-methylcytosine (5-mC) has been extensively studied, little is...
Chemical modifications of DNA comprise epigenetic mechanisms that contribute to the maintenance of cellular activities and memory. Although the function of 5-methylcytosine (5-mC) has been extensively studied, little is known about the function(s) of relatively rarer and underappreciated cytosine modifications including 5-hydroxymethylcytosine (5-hmC). The discovery that ten-eleven translocation (Tet) proteins mediate conversion of 5-mC to 5-hmC, and other oxidation derivatives, sparked renewed interest to understand the biological role of 5-hmC. Studies examining total 5-hmC levels revealed the highly dynamic yet tissue-specific nature of this modification, implicating a role in epigenetic regulation and development. Intriguingly, 5-hmC levels are highest during early development and in the brain where abnormal patterns of 5-hmC have been observed in disease conditions. Thus, 5-hmC adds to the growing list of epigenetic modifications with potential utility in clinical applications and warrants further investigation. This review discusses the emerging functional roles of 5-hmC in normal and disease states, focusing primarily on insights provided by recent studies exploring the genome-wide distribution of this modification in mammals.
Obesity: epigenetic aspects.
Kaushik P, Anderson JT
Biomol Concepts · 2016 Jun · PMID 27327133 · Publisher ↗
Epigenetics, defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence has been shown to play an important role in the etiopathogenesis of obesity. Obe...
Epigenetics, defined as inheritable and reversible phenomena that affect gene expression without altering the underlying base pair sequence has been shown to play an important role in the etiopathogenesis of obesity. Obesity is associated with extensive gene expression changes in tissues throughout the body. Epigenetics is emerging as perhaps the most important mechanism through which the lifestyle-choices we make can directly influence the genome. Considerable epidemiological, experimental and clinical data have been amassed showing that the risk of developing disease in later life is dependent on early life conditions, mainly operating within the normative range of developmental exposures. In addition to the 'maternal' interactions, there has been increasing interest in the epigenetic mechanisms through which 'paternal' influences on offspring development can be achieved. Nutrition, among many other environmental factors, is a key player that can induce epigenetic changes not only in the directly exposed organisms but also in subsequent generations through the transgenerational inheritance of epigenetic traits. Overall, significant progress has been made in the field of epigenetics and obesity and the first potential epigenetic markers for obesity that could be detected at birth have been identified. Fortunately, epigenetic phenomena are dynamic and rather quickly reversible with intensive lifestyle changes. This is a very promising and sustainable resolution to the obesity pandemic.
The sensing of bacteria: emerging principles for the detection of signal sequences by formyl peptide receptors.
Bufe B, Zufall F
Biomol Concepts · 2016 Jun · PMID 27305707 · Publisher ↗
The ability to detect specific chemical signatures released by bacteria and other microorganisms is a fundamental feature of immune defense against pathogens. There is increasing evidence that chemodetection of such micr...
The ability to detect specific chemical signatures released by bacteria and other microorganisms is a fundamental feature of immune defense against pathogens. There is increasing evidence that chemodetection of such microorganism-associated molecular patterns (MAMPs) occurs at many places in the body including specific sets of chemosensory neurons in the mammalian nose. Formyl peptide receptors (FPRs) are a unique family of G protein-coupled receptors (GPCRs) that can detect the presence of bacteria and function as chemotactic receptors. Here, we highlight the recent discovery of a vast family of natural FPR agonists, the bacterial signal peptides (or signal sequences), thus providing new insight into the molecular mechanisms of bacterial sensing by human and mouse FPRs. Signal peptides in bacteria are formylated, N-terminal protein signatures required for directing the transfer of proteins through the plasma membrane. After their cleavage and release, signal peptides are available for FPR detection and thus provide a previously unrecognized MAMP. With over 170 000 predicted sequences, bacterial signal peptides represent one of the largest families of GPCR ligands and one of the most complex classes of natural activators of the innate immune system. By recognizing a conserved three-dimensional peptide motif, FPRs employ an unusual detection mechanism that combines structural promiscuity with high specificity and sensitivity, thus solving the problem of detecting thousands of distinct sequences yet maintaining selectivity. How signal peptides are released by bacteria and sensed by GPCRs and how these processes shape the responses of other cells and whole organisms represents an important topic for future research.
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