Formyl peptide receptor
Encyclopedia
The formyl peptide receptors (FPR) are a members of a class of G protein-coupled receptor
s involved in chemotaxis
. These receptors where originally identified by their ability to bind N-formyl peptides such as N-formylmethionine
produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetical relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ
chemosensors in mice
of the FPR is stabilized by several interactions. These include potential salt bridge
formation between Arg84-Arg205, Lys85-Arg205, and Lys85-Asp284 which help determine the three-dimensional structure of transmembrane domains, as well as positively charged residues (Arg, Lys) which interact with negatively charged phosphates. Furthermore residue Arg163 may interact with the ligand binding pocket of the second extracellular loop of the FPR.
With respect to binding of the formyl Met-Leu-Phe peptide, there are additional potential interactions which include hydrogen bond
ing interactions between Arg84 and Lys85 of the first extracellular loop and the N-formyl group of the ligand as well as the peptide backbone of formyl Met-Leu-Phe which can form similar interactions. The formyl-Met moiety
of the ligand was shown to form disulfide bridges with Cys residues, and an interaction with Arg163 was also demonstrated. (It is important to mention that some interaction which stabilize the conformation of the receptor may also influence ligand-binding.) Some oligopeptides were also described as characteristic constituents linked to Asn-s of the extracellular N terminal part and to the ligand binding pocket of the second extracellular loop. These components can also determine or make more specific the ligand-receptor interaction.
cells including rearrangement of the cytoskeleton
which in turn facilitates cell migration and the synthesis of chemokine
s.
Important FPR regulated pathways include:
G protein-coupled receptor
G protein-coupled receptors , also known as seven-transmembrane domain receptors, 7TM receptors, heptahelical receptors, serpentine receptor, and G protein-linked receptors , comprise a large protein family of transmembrane receptors that sense molecules outside the cell and activate inside signal...
s involved in chemotaxis
Chemotaxis
Chemotaxis is the phenomenon in which somatic cells, bacteria, and other single-cell or multicellular organisms direct their movements according to certain chemicals in their environment. This is important for bacteria to find food by swimming towards the highest concentration of food molecules,...
. These receptors where originally identified by their ability to bind N-formyl peptides such as N-formylmethionine
N-Formylmethionine
N-Formylmethionine is a proteinogenic amino acid found in Bacteria and related Prokaryotic organelles. It is a derivative of the amino acid methionine in which a formyl group has been added to the amino group...
produced by the degradation of either bacterial or host cells. Hence formyl peptide receptors are involved in mediating immune cell response to infection. These receptors may also act to suppress the immune system under certain conditions. The close phylogenetical relation of signaling in chemotaxis and olfaction was recently proved by detection formyl peptide receptor like proteins as a distinct family of vomeronasal organ
Vomeronasal organ
The vomeronasal organ , or Jacobson's organ, is an auxiliary olfactory sense organ that is found in many animals. It was discovered by Frederik Ruysch and later by Ludwig Jacobson in 1813....
chemosensors in mice
Structure - function
The formyl peptide receptor (FPR) belongs to the class of receptors possessing seven hydrophobic transmembrane domains. The conformationProtein structure
Proteins are an important class of biological macromolecules present in all organisms. Proteins are polymers of amino acids. Classified by their physical size, proteins are nanoparticles . Each protein polymer – also known as a polypeptide – consists of a sequence formed from 20 possible L-α-amino...
of the FPR is stabilized by several interactions. These include potential salt bridge
Salt bridge (protein)
Salt bridges fall into the broader category of noncovalent interactions. A salt bridge is actually a combination of two noncovalent interactions: hydrogen bonding and electrostatic interactions . This is most commonly observed to contribute stability to the entropically unfavorable folded...
formation between Arg84-Arg205, Lys85-Arg205, and Lys85-Asp284 which help determine the three-dimensional structure of transmembrane domains, as well as positively charged residues (Arg, Lys) which interact with negatively charged phosphates. Furthermore residue Arg163 may interact with the ligand binding pocket of the second extracellular loop of the FPR.
With respect to binding of the formyl Met-Leu-Phe peptide, there are additional potential interactions which include hydrogen bond
Hydrogen bond
A hydrogen bond is the attractive interaction of a hydrogen atom with an electronegative atom, such as nitrogen, oxygen or fluorine, that comes from another molecule or chemical group. The hydrogen must be covalently bonded to another electronegative atom to create the bond...
ing interactions between Arg84 and Lys85 of the first extracellular loop and the N-formyl group of the ligand as well as the peptide backbone of formyl Met-Leu-Phe which can form similar interactions. The formyl-Met moiety
Functional group
In organic chemistry, functional groups are specific groups of atoms within molecules that are responsible for the characteristic chemical reactions of those molecules. The same functional group will undergo the same or similar chemical reaction regardless of the size of the molecule it is a part of...
of the ligand was shown to form disulfide bridges with Cys residues, and an interaction with Arg163 was also demonstrated. (It is important to mention that some interaction which stabilize the conformation of the receptor may also influence ligand-binding.) Some oligopeptides were also described as characteristic constituents linked to Asn-s of the extracellular N terminal part and to the ligand binding pocket of the second extracellular loop. These components can also determine or make more specific the ligand-receptor interaction.
Signaling pathways
Induction of FPR triggers multiple changes in eukaryoticEukaryote
A eukaryote is an organism whose cells contain complex structures enclosed within membranes. Eukaryotes may more formally be referred to as the taxon Eukarya or Eukaryota. The defining membrane-bound structure that sets eukaryotic cells apart from prokaryotic cells is the nucleus, or nuclear...
cells including rearrangement of the cytoskeleton
Cytoskeleton
The cytoskeleton is a cellular "scaffolding" or "skeleton" contained within a cell's cytoplasm and is made out of protein. The cytoskeleton is present in all cells; it was once thought to be unique to eukaryotes, but recent research has identified the prokaryotic cytoskeleton...
which in turn facilitates cell migration and the synthesis of chemokine
Chemokine
Chemokines are a family of small cytokines, or proteins secreted by cells. Their name is derived from their ability to induce directed chemotaxis in nearby responsive cells; they are chemotactic cytokines...
s.
Important FPR regulated pathways include:
- G proteinG proteinG proteins are a family of proteins involved in transmitting chemical signals outside the cell, and causing changes inside the cell. They communicate signals from many hormones, neurotransmitters, and other signaling factors. G protein-coupled receptors are transmembrane receptors...
dependent activation of phospholipase CPhospholipase CPhosphoinositide phospholipase C is a family of eukaryotic intracellular enzymes that play an important role in signal transduction processes. In general, this enzyme is denoted as Phospholipase C, although three other families of phospholipase C enzymes have been identified in bacteria and in...
(PLC) which results in the breakdown of the membrane constituent phospholipid, phosphatidylinositol (4,5)-bisphosphatePhosphatidylinositol (4,5)-bisphosphatePhosphatidylinositol 4,5-bisphosphate or PtdInsP2, also known simply as PIP2, is a minor phospholipid component of cell membranes...
(PIP2) into phosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol (3,4,5)-trisphosphatePhosphatidylinositol -triphosphate , abbreviated PIP3, is the product of the class I phosphoinositide 3-kinases phosphorylation on phosphatidylinositol -bisphosphate .-Discovery:...
(IP3) and diacyl glycerol (DAG). IP3 is one of the most effective inducer of Ca2+ increase from cytoplasmic pools and from outside the cell via opening Ca2+ channelsCalcium channelA Calcium channel is an ion channel which displays selective permeability to calcium ions. It is sometimes synonymous as voltage-dependent calcium channel, although there are also ligand-gated calcium channels.-Comparison tables:...
. DAG in turn is an inducer of protein kinase CProtein kinase CProtein kinase C also known as PKC is a family of enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins. PKC enzymes in turn are activated by signals such as increases in...
(PKC). - Activation of the regulatory small GTPase, RAS. The active RAS can in turn activate RAFC-RafRAF proto-oncogene serine/threonine-protein kinase also known as proto-oncogene c-RAF or simply c-Raf is an enzyme that in humans is encoded by the RAF1 gene. The c-Raf protein functions in the MAPK/ERK signal transduction pathway as part of a protein kinase cascade...
, a Ser/Thr kinase. In the next step mitogen-activated protein kinaseMitogen-activated protein kinaseMitogen-activated protein kinases are serine/threonine-specific protein kinases that respond to extracellular stimuli and regulate various cellular activities, such as gene expression, mitosis, differentiation, proliferation, and cell survival/apoptosis.-Activation:MAP kinases are activated...
s (MAP kinases) are activated. (Also known as extracellular signal-regulated kinases - ERKsExtracellular signal-regulated kinasesIn molecular biology, extracellular-signal-regulated kinases or classical MAP kinases are widely expressed protein kinase intracellular signalling molecules that are involved in functions including the regulation of meiosis, mitosis, and postmitotic functions in differentiated cells...
or MAP/ERK kinase (MEK)). As a result of the last step, ERK1MAPK3Mitogen-activated protein kinase 3 is an enzyme that in humans is encoded by the MAPK3 gene.-Interactions:MAPK3 has been shown to interact with PTPN7, SPIB, GTF2I, DUSP3, HDAC4, RPS6KA2, MAP2K1, DUSP6 and MAP2K2.-Further reading:...
and ERK2MAPK1Mitogen-activated protein kinase 1, also known as MAPK1, p42MAPK, and ERK2, is an enzyme that in humans is encoded by the MAPK1 gene.- Function :The protein encoded by this gene is a member of the MAP kinase family...
are activated. The phosphorylated forms of ERKs can continue the cascade by triggering activation more interacting kinases which results in altered transcriptional activity in the nucleus. - Ligand binding to FPR can also induce the activation of CD38CD38CD38 , also known as cyclic ADP ribose hydrolase is a glycoprotein found on the surface of many immune cells , including CD4+, CD8+, B and natural killer cells...
, an ectoenzyme of the surface membrane. As a result of activation NAD+Nicotinamide adenine dinucleotideNicotinamide adenine dinucleotide, abbreviated NAD, is a coenzyme found in all living cells. The compound is a dinucleotide, since it consists of two nucleotides joined through their phosphate groups. One nucleotide contains an adenine base and the other nicotinamide.In metabolism, NAD is involved...
molecules will enter the cytoplasm. NAD+ is converted into cyclic ADP ribose (cADPR), a second messenger which interacts with ryanodine receptorRyanodine receptorRyanodine receptors form a class of intracellular calcium channels in various forms of excitable animal tissue like muscles and neurons...
s (RyR) on the surface of the rough endoplasmic reticulum. The overal result of the process is increased cytoplasmic Ca2+ levels via the direct pathway described above and also via indirect pathways such as opening of Ca2+ channels in the cell membrane. The sustained increase of Ca2+ is required for directed migration of the cells.