Protein targeting
Encyclopedia
Protein targeting or protein sorting is the mechanism by which a cell
transports protein
s to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle
, any of several interior membrane
s, the cell's outer membrane
, or its exterior via secretion
. This delivery process is carried out based on information contained in the protein itself. Correct sorting is crucial for the cell; errors can lead to diseases.
or in the folded protein. The continuous stretch of amino acid
residues in the chain that enables targeting are called signal peptide
s or targeting peptides. There are two types of targeting peptides, the presequences and the internal targeting peptides. The presequences of the targeting peptide are often found at the N-terminal extension and is composed of between 6-136 basic and hydrophobic amino acids.In case of peroxisomes the targeting sequence is on the C-terminal extension mostly. Other signals are composed by parts which are separate in the primary sequence. To function, these components have to come together on the protein surface by folding
. They are called signal patches. In addition, protein modifications
like glycosylations can induce targeting.
conducted experiments on the translocation of proteins across membranes. He was awarded the 1999 Nobel prize
for his findings. He discovered that many proteins have a signal sequence
, that is, a short amino acid
sequence at one end that functions like a postal code
for the target organelle. The translation of mRNA into protein by a ribosome
takes place within the cytosol
. If the synthesized proteins "belong" in a different organelle, they can be transported there in either of two ways depending on the protein: Cotranslational translocation (translocation during the process of translation) Posttranslational translocation (transloaction after the process of translation is complete).
(SRP) while the protein is still being synthesized on the ribosome. The synthesis pauses while the ribosome-protein complex is transferred to a SRP receptor
on the endoplasmic reticulum
(ER), a membrane-enclosed organelle. There, the nascent protein is inserted into the Sec61 translocation complex
(also known as the translocon) that passes through the ER membrane. In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the ER by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold
correctly. Once folded, the protein is modified as needed (for example, by glycosylation
), then transported to the Golgi apparatus
for further processing and goes to its target organelles or is retained in the ER by various ER retention
mechanisms.
The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. They are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor sequence. These complex membrane proteins are at the moment mostly understood using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit the model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genome of humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This would seem to break the rule of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. This has been demonstrated with opsin
with in vitro experiments. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.
and later transported to their destination. This occurs for proteins that go to a mitochondrion
, a chloroplast
, or a peroxisome
(proteins that go to the latter have their signal sequence at the C terminus). Also, proteins targeted for the nucleus
are translocated post-translation. They pass through the nuclear envelope
via nuclear pore
s.
protein
s are synthesized as cytosolic precursors containing uptake peptide signals. Cytosolic chaperones deliver preproteins to channel linked receptors in the mitochondrial membrane. The preprotein with presequence targeted for the mitochondria is bound by receptors
and the General Import Pore (GIP) (Receptors and GIP are collectively known as Translocase of Outer Membrane or TOM) at the outer membrane
. The preprotein is translocated through TOM as hairpin loops. The preprotein is transported through the intermembrane space
by small TIMs (which also acts as molecular chaperones) to the TIM23 or 22 (Translocase of Inner Membrane) at the inner membrane
. Within the matrix
the targeting sequence is cleaved off by mtHsp70.
Three mitochondrial outer membrane receptors
are known: TOM20, TOM22 and TOM70
TOM70: Binds to internal targeting peptides and acts as a docking point for cytosolic chaperones.
TOM20: Binds presequences
TOM22: Binds both presequences and internal targeting peptides
The TOM channel is a cation specific high conductance channel with a molecular weight of 410 kDa
and a pore diameter
of 21Å.
The presequence translocase23 (TIM23) is localized to the mitochondial inner membrane
and acts a pore forming protein which binds precursor proteins with its N-terminal. TIM23 acts a translocator for preproteins for the mitochondrial matrix, the inner mitochondrial membrane as well as for the intermembrane space. TIM50 is bound to TIM23 at the inner mitochondrial side and found to bind presequences. TIM44 is bound on the matrix side and found binding to mtHsp70.
The presequence translocase22 (TIM22) binds preproteins exclusively bound for the inner mitochondrial membrane.
Mitochondrial matrix
targeting sequences are rich in positively charged amino acids and hydroxylated ones.
Proteins are targeted to submitochondrial compartments by multiple signals and several pathways.
Targeting to the outer membrane, intermembrane space
, and inner membrane often requires another signal sequence in addition to the matrix targeting sequence.
s may contain a stromal import sequence or a stromal and thylakoid targeting sequence. The majority of preproteins are translocated through the Toc and Tic complexes located within the chloroplast envelope. In the stroma the stromal import sequence is cleaved off and folding as well as intra-chloroplast sorting to thylakoid
s continues. Proteins targeted to the envelope of chloroplasts usually lack cleavable sorting sequence.
proteins are encoded by nuclear genes.
To date there are two types of known Peroxisome Targeting Signals (PTS):
Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine
-lysine
-leucine
(SKL). Most peroxisomal matrix proteins possess a PTS1 type signal.
Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid).
There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them.
coated pits on the outside of cells cause the cell to perform endocytosis
, an invagination of the plasma membrane to incorporate the molecule and associated structures into endosomes. This mechanism is used for three main purposes:
Receptor-mediated endocytosis can also be "abused":
.
In most Gram-positive bacteria, certain proteins are targeted for export across the plasma membrane and subsequent covalent attachment to the bacterial cell wall. A specialized enzyme, sortase
, cleaves the target protein at a characteristic recognition site near the protein C-terminus, such as an LPXTG motif (where X can be any amino acid), then transfers the protein onto the cell wall. An system analogous to sortase/LPXTG, termed exosortase/PEP-CTERM, is proposed to exist in a broad range of Gram-negative bacteria.
includes vesicular traffic, secretion, and endocytosis. Secretory protein
s follow this pathway.
advance through cisternal progression.
is a bioinformatics tool that searches protein sequence queries for a known protein targeting sequence motifs.
Cell (biology)
The cell is the basic structural and functional unit of all known living organisms. It is the smallest unit of life that is classified as a living thing, and is often called the building block of life. The Alberts text discusses how the "cellular building blocks" move to shape developing embryos....
transports protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s to the appropriate positions in the cell or outside of it. Sorting targets can be the inner space of an organelle
Organelle
In cell biology, an organelle is a specialized subunit within a cell that has a specific function, and is usually separately enclosed within its own lipid bilayer....
, any of several interior membrane
Biological membrane
A biological membrane or biomembrane is an enclosing or separatingmembrane that acts as a selective barrier, within or around a cell. It consists of a lipid bilayer with embedded proteins that may constitute close to 50% of membrane content...
s, the cell's outer membrane
Cell membrane
The cell membrane or plasma membrane is a biological membrane that separates the interior of all cells from the outside environment. The cell membrane is selectively permeable to ions and organic molecules and controls the movement of substances in and out of cells. It basically protects the cell...
, or its exterior via secretion
Secretion
Secretion is the process of elaborating, releasing, and oozing chemicals, or a secreted chemical substance from a cell or gland. In contrast to excretion, the substance may have a certain function, rather than being a waste product...
. This delivery process is carried out based on information contained in the protein itself. Correct sorting is crucial for the cell; errors can lead to diseases.
Targeting signals
Targeting signals are the pieces of information that enable the cellular transport machinery to correctly position a protein inside or outside the cell. This information is contained in the polypeptide chainPrimary structure
The primary structure of peptides and proteins refers to the linear sequence of its amino acid structural units. The term "primary structure" was first coined by Linderstrøm-Lang in 1951...
or in the folded protein. The continuous stretch of amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
residues in the chain that enables targeting are called signal peptide
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
s or targeting peptides. There are two types of targeting peptides, the presequences and the internal targeting peptides. The presequences of the targeting peptide are often found at the N-terminal extension and is composed of between 6-136 basic and hydrophobic amino acids.In case of peroxisomes the targeting sequence is on the C-terminal extension mostly. Other signals are composed by parts which are separate in the primary sequence. To function, these components have to come together on the protein surface by folding
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
. They are called signal patches. In addition, protein modifications
Posttranslational modification
Posttranslational modification is the chemical modification of a protein after its translation. It is one of the later steps in protein biosynthesis, and thus gene expression, for many proteins....
like glycosylations can induce targeting.
Protein translocation
In 1970, Günter BlobelGünter Blobel
-Biography:Blobel was born in Waltersdorf in the Prussian Province of Lower Silesia. In January 1945 his family fled from native Silesia from the advancing Red Army. On their way to the West they passed through the beautiful old city of Dresden, which left deep impressions in the young boy...
conducted experiments on the translocation of proteins across membranes. He was awarded the 1999 Nobel prize
Nobel Prize in Physiology or Medicine
The Nobel Prize in Physiology or Medicine administered by the Nobel Foundation, is awarded once a year for outstanding discoveries in the field of life science and medicine. It is one of five Nobel Prizes established in 1895 by Swedish chemist Alfred Nobel, the inventor of dynamite, in his will...
for his findings. He discovered that many proteins have a signal sequence
Signal peptide
A signal peptide is a short peptide chain that directs the transport of a protein.Signal peptides may also be called targeting signals, signal sequences, transit peptides, or localization signals....
, that is, a short amino acid
Amino acid
Amino acids are molecules containing an amine group, a carboxylic acid group and a side-chain that varies between different amino acids. The key elements of an amino acid are carbon, hydrogen, oxygen, and nitrogen...
sequence at one end that functions like a postal code
Postal code
A postal code is a series of letters and/or digits appended to a postal address for the purpose of sorting mail. Once postal codes were introduced, other applications became possible.In February 2005, 117 of the 190 member countries of the Universal Postal Union had postal code systems...
for the target organelle. The translation of mRNA into protein by a ribosome
Ribosome
A ribosome is a component of cells that assembles the twenty specific amino acid molecules to form the particular protein molecule determined by the nucleotide sequence of an RNA molecule....
takes place within the cytosol
Cytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
. If the synthesized proteins "belong" in a different organelle, they can be transported there in either of two ways depending on the protein: Cotranslational translocation (translocation during the process of translation) Posttranslational translocation (transloaction after the process of translation is complete).
Cotranslational translocation
The N-terminal signal sequence of the protein is recognized by a signal recognition particleSignal recognition particle
The signal recognition particle is an abundant, cytosolic, universally conserved ribonucleoprotein that recognizes and targets specific proteins to the endoplasmic reticulum in eukaryotes and the plasma membrane in prokaryotes....
(SRP) while the protein is still being synthesized on the ribosome. The synthesis pauses while the ribosome-protein complex is transferred to a SRP receptor
SRP receptor
Signal recognition particle receptor, also called docking protein, is a dimer composed of 2 different subunits that are associated exclusively with the rough ER in mammalian cells. Its main function is to identify the SRP units...
on the endoplasmic reticulum
Endoplasmic reticulum
The endoplasmic reticulum is an organelle of cells in eukaryotic organisms that forms an interconnected network of tubules, vesicles, and cisternae...
(ER), a membrane-enclosed organelle. There, the nascent protein is inserted into the Sec61 translocation complex
Sec61
Sec61 is an endoplasmic reticulum membrane protein translocator . It is a doughnut shaped pore through the membrane with 3 major subunits . It has a region called the plug that blocks transport into or out of the ER...
(also known as the translocon) that passes through the ER membrane. In secretory proteins and type I transmembrane proteins, the signal sequence is immediately cleaved from the nascent polypeptide once it has been translocated into the ER by signal peptidase. The signal sequence of type II membrane proteins and some polytopic membrane proteins are not cleaved off and therefore are referred to as signal anchor sequences. Within the ER, the protein is first covered by a chaperone protein to protect it from the high concentration of other proteins in the ER, giving it time to fold
Protein folding
Protein folding is the process by which a protein structure assumes its functional shape or conformation. It is the physical process by which a polypeptide folds into its characteristic and functional three-dimensional structure from random coil....
correctly. Once folded, the protein is modified as needed (for example, by glycosylation
Glycosylation
Glycosylation is the reaction in which a carbohydrate, i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule . In biology glycosylation refers to the enzymatic process that attaches glycans to proteins, lipids, or other organic molecules...
), then transported to the Golgi apparatus
Golgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
for further processing and goes to its target organelles or is retained in the ER by various ER retention
ER retention
ER retention refers to proteins that are retained in the endoplasmic reticulum, or ER, after folding; these are known as ER resident proteins....
mechanisms.
The amino acid chain of transmembrane proteins, which often are transmembrane receptors, passes through a membrane one or several times. They are inserted into the membrane by translocation, until the process is interrupted by a stop-transfer sequence, also called a membrane anchor sequence. These complex membrane proteins are at the moment mostly understood using the same model of targeting that has been developed for secretory proteins. However, many complex multi-transmembrane proteins contain structural aspects that do not fit the model. Seven transmembrane G-protein coupled receptors (which represent about 5% of the genome of humans) mostly do not have an amino-terminal signal sequence. In contrast to secretory proteins, the first transmembrane domain acts as the first signal sequence, which targets them to the ER membrane. This also results in the translocation of the amino terminus of the protein into the ER membrane lumen. This would seem to break the rule of "co-translational" translocation which has always held for mammalian proteins targeted to the ER. This has been demonstrated with opsin
Opsin
Opsins are a group of light-sensitive 35–55 kDa membrane-bound G protein-coupled receptors of the retinylidene protein family found in photoreceptor cells of the retina. Five classical groups of opsins are involved in vision, mediating the conversion of a photon of light into an electrochemical...
with in vitro experiments. A great deal of the mechanics of transmembrane topology and folding remains to be elucidated.
Posttranslational translocation
Even though most proteins are cotranslationally translocated, some are translated in the cytosolCytosol
The cytosol or intracellular fluid is the liquid found inside cells, that is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondrion into compartments....
and later transported to their destination. This occurs for proteins that go to a mitochondrion
Mitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
, a chloroplast
Chloroplast
Chloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...
, or a peroxisome
Peroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
(proteins that go to the latter have their signal sequence at the C terminus). Also, proteins targeted for the nucleus
Cell nucleus
In cell biology, the nucleus is a membrane-enclosed organelle found in eukaryotic cells. It contains most of the cell's genetic material, organized as multiple long linear DNA molecules in complex with a large variety of proteins, such as histones, to form chromosomes. The genes within these...
are translocated post-translation. They pass through the nuclear envelope
Nuclear envelope
A nuclear envelope is a double lipid bilayer that encloses the genetic material in eukaryotic cells. The nuclear envelope also serves as the physical barrier, separating the contents of the nucleus from the cytosol...
via nuclear pore
Nuclear pore
Nuclear pores are large protein complexes that cross the nuclear envelope, which is the double membrane surrounding the eukaryotic cell nucleus. There are about on average 2000 nuclear pore complexes in the nuclear envelope of a vertebrate cell, but it varies depending on cell type and the stage in...
s.
Sorting of proteins to mitochondria
Most mitochondrialMitochondrion
In cell biology, a mitochondrion is a membrane-enclosed organelle found in most eukaryotic cells. These organelles range from 0.5 to 1.0 micrometers in diameter...
protein
Protein
Proteins are biochemical compounds consisting of one or more polypeptides typically folded into a globular or fibrous form, facilitating a biological function. A polypeptide is a single linear polymer chain of amino acids bonded together by peptide bonds between the carboxyl and amino groups of...
s are synthesized as cytosolic precursors containing uptake peptide signals. Cytosolic chaperones deliver preproteins to channel linked receptors in the mitochondrial membrane. The preprotein with presequence targeted for the mitochondria is bound by receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
and the General Import Pore (GIP) (Receptors and GIP are collectively known as Translocase of Outer Membrane or TOM) at the outer membrane
Outer membrane
The bacterial outer membrane is found in Gram-negative bacteria. Its composition is distinct from that of the cytoplasmic membrane - among other things, the outer leaflet of the membrane includes a complex lipopolysaccharide whose lipid portion acts as an endotoxin - and it is linked to the cell's...
. The preprotein is translocated through TOM as hairpin loops. The preprotein is transported through the intermembrane space
Intermembrane space
The intermembrane space also known as IMS is the region between the inner membrane and the outer membrane of a mitochondrion or a chloroplast. The main function of the intermembrane space is oxidative phosphorylation....
by small TIMs (which also acts as molecular chaperones) to the TIM23 or 22 (Translocase of Inner Membrane) at the inner membrane
Inner membrane
The inner membrane is the biological membrane of an organelle or Gram-negative bacteria that is within an outer membrane....
. Within the matrix
Matrix (biology)
In biology, matrix is the material between animal or plant cells, in which more specialized structures are embedded, and a specific part of the mitochondrion that is the site of oxidation of organic molecules. The internal structure of connective tissues is an extracellular matrix...
the targeting sequence is cleaved off by mtHsp70.
Three mitochondrial outer membrane receptors
Receptor (biochemistry)
In biochemistry, a receptor is a molecule found on the surface of a cell, which receives specific chemical signals from neighbouring cells or the wider environment within an organism...
are known: TOM20, TOM22 and TOM70
TOM70: Binds to internal targeting peptides and acts as a docking point for cytosolic chaperones.
TOM20: Binds presequences
TOM22: Binds both presequences and internal targeting peptides
The TOM channel is a cation specific high conductance channel with a molecular weight of 410 kDa
KDA
KDA may refer to:* Karachi Development Authority* Kongsberg Defence & Aerospace* Kotelawala Defence Academy* Kramer Design Associates* Lithium diisopropylamide, KDA is the potassium analogue of lithium diisopropylamideOr kDa may refer to:...
and a pore diameter
Diameter
In geometry, a diameter of a circle is any straight line segment that passes through the center of the circle and whose endpoints are on the circle. The diameters are the longest chords of the circle...
of 21Å.
The presequence translocase23 (TIM23) is localized to the mitochondial inner membrane
Inner membrane
The inner membrane is the biological membrane of an organelle or Gram-negative bacteria that is within an outer membrane....
and acts a pore forming protein which binds precursor proteins with its N-terminal. TIM23 acts a translocator for preproteins for the mitochondrial matrix, the inner mitochondrial membrane as well as for the intermembrane space. TIM50 is bound to TIM23 at the inner mitochondrial side and found to bind presequences. TIM44 is bound on the matrix side and found binding to mtHsp70.
The presequence translocase22 (TIM22) binds preproteins exclusively bound for the inner mitochondrial membrane.
Mitochondrial matrix
Mitochondrial matrix
In the mitochondrion, the matrix contains soluble enzymes that catalyze the oxidation of pyruvate and other small organic molecules.The mitochondrial matrix also contains the mitochondria's DNA and ribosomes. The word "matrix" stems from the fact that this space is viscous, compared to the...
targeting sequences are rich in positively charged amino acids and hydroxylated ones.
Proteins are targeted to submitochondrial compartments by multiple signals and several pathways.
Targeting to the outer membrane, intermembrane space
Intermembrane space
The intermembrane space also known as IMS is the region between the inner membrane and the outer membrane of a mitochondrion or a chloroplast. The main function of the intermembrane space is oxidative phosphorylation....
, and inner membrane often requires another signal sequence in addition to the matrix targeting sequence.
Sorting of proteins to chloroplasts
The preprotein for chloroplastChloroplast
Chloroplasts are organelles found in plant cells and other eukaryotic organisms that conduct photosynthesis. Chloroplasts capture light energy to conserve free energy in the form of ATP and reduce NADP to NADPH through a complex set of processes called photosynthesis.Chloroplasts are green...
s may contain a stromal import sequence or a stromal and thylakoid targeting sequence. The majority of preproteins are translocated through the Toc and Tic complexes located within the chloroplast envelope. In the stroma the stromal import sequence is cleaved off and folding as well as intra-chloroplast sorting to thylakoid
Thylakoid
A thylakoid is a membrane-bound compartment inside chloroplasts and cyanobacteria. They are the site of the light-dependent reactions of photosynthesis. Thylakoids consist of a thylakoid membrane surrounding a thylakoid lumen. Chloroplast thylakoids frequently form stacks of disks referred to as...
s continues. Proteins targeted to the envelope of chloroplasts usually lack cleavable sorting sequence.
Sorting of proteins to both chloroplasts and mitochondria
Many proteins are needed in both mitochondria and chloroplasts. In general the targeting peptide is of intermediate character to the two specific ones. The targeting peptides of these proteins have a high content of basic and hydrophobic amino acids, a low content of negatively charged amino acids. They have a lower content of alanine and a higher content of leucine and phenylalanine. The dual targeted proteins have a more hydrophobic targeting peptide than both mitochondrial and chloroplastic ones.Sorting of proteins to peroxisomes
All peroxisomalPeroxisome
Peroxisomes are organelles found in virtually all eukaryotic cells. They are involved in the catabolism of very long chain fatty acids, branched chain fatty acids, D-amino acids, polyamines, and biosynthesis of plasmalogens, etherphospholipids critical for the normal function of mammalian brains...
proteins are encoded by nuclear genes.
To date there are two types of known Peroxisome Targeting Signals (PTS):
Peroxisome targeting signal 1 (PTS1): a C-terminal tripeptide with a consensus sequence (S/A/C)-(K/R/H)-(L/A). The most common PTS1 is serine
Serine
Serine is an amino acid with the formula HO2CCHCH2OH. It is one of the proteinogenic amino acids. By virtue of the hydroxyl group, serine is classified as a polar amino acid.-Occurrence and biosynthesis:...
-lysine
Lysine
Lysine is an α-amino acid with the chemical formula HO2CCH4NH2. It is an essential amino acid, which means that the human body cannot synthesize it. Its codons are AAA and AAG....
-leucine
Leucine
Leucine is a branched-chain α-amino acid with the chemical formula HO2CCHCH2CH2. Leucine is classified as a hydrophobic amino acid due to its aliphatic isobutyl side chain. It is encoded by six codons and is a major component of the subunits in ferritin, astacin and other 'buffer' proteins...
(SKL). Most peroxisomal matrix proteins possess a PTS1 type signal.
Peroxisome targeting signal 2 (PTS2): a nonapeptide located near the N-terminus with a consensus sequence (R/K)-(L/V/I)-XXXXX-(H/Q)-(L/A/F) (where X can be any amino acid).
There are also proteins that possess neither of these signals. Their transport may be based on a so-called "piggy-back" mechanism: such proteins associate with PTS1-possessing matrix proteins and are translocated into the peroxisomal matrix together with them.
Diseases
Peroxisomal protein transport is defective in the following genetic diseases:- Zellweger syndromeZellweger syndromeZellweger syndrome, also called cerebrohepatorenal syndrome is a rare, congenital disorder, characterized by the reduction or absence of functional peroxisomes in the cells of an individual. It is one of a family of disorders called leukodystrophies...
. - AdrenoleukodystrophyAdrenoleukodystrophyAdrenoleukodystrophy is a rare, inherited disorder that leads to progressive brain damage, failure of the adrenal glands and eventually death. ALD is a disease in a group of genetic disorders called leukodystrophies, whose chief feature is damage to myelin...
(ALD). - Refsum disease
Receptor-mediated endocytosis
Several molecules that attach to special receptors called clathrinClathrin
Clathrin is a protein that plays a major role in the formation of coated vesicles. Clathrin was first isolated and named by Barbara Pearse in 1975. It forms a triskelion shape composed of three clathrin heavy chains and three light chains. When the triskelia interact they form a polyhedral lattice...
coated pits on the outside of cells cause the cell to perform endocytosis
Endocytosis
Endocytosis is a process by which cells absorb molecules by engulfing them. It is used by all cells of the body because most substances important to them are large polar molecules that cannot pass through the hydrophobic plasma or cell membrane...
, an invagination of the plasma membrane to incorporate the molecule and associated structures into endosomes. This mechanism is used for three main purposes:
- Uptake of essential metabolites, for example, LDL.
- Uptake of some hormoneHormoneA hormone is a chemical released by a cell or a gland in one part of the body that sends out messages that affect cells in other parts of the organism. Only a small amount of hormone is required to alter cell metabolism. In essence, it is a chemical messenger that transports a signal from one...
s and growth factorGrowth factorA growth factor is a naturally occurring substance capable of stimulating cellular growth, proliferation and cellular differentiation. Usually it is a protein or a steroid hormone. Growth factors are important for regulating a variety of cellular processes....
s, for example, epidermal growth factorEpidermal growth factorEpidermal growth factor or EGF is a growth factor that plays an important role in the regulation of cell growth, proliferation, and differentiation by binding to its receptor EGFR...
and nerve growth factorNerve growth factorNerve growth factor is a small secreted protein that is important for the growth, maintenance, and survival of certain target neurons . It also functions as a signaling molecule. It is perhaps the prototypical growth factor, in that it is one of the first to be described...
. - Uptake of proteins that are to be destroyed, for example, antigenAntigenAn antigen is a foreign molecule that, when introduced into the body, triggers the production of an antibody by the immune system. The immune system will then kill or neutralize the antigen that is recognized as a foreign and potentially harmful invader. These invaders can be molecules such as...
s in phagocytotic cells like macrophageMacrophageMacrophages are cells produced by the differentiation of monocytes in tissues. Human macrophages are about in diameter. Monocytes and macrophages are phagocytes. Macrophages function in both non-specific defense as well as help initiate specific defense mechanisms of vertebrate animals...
s.
Receptor-mediated endocytosis can also be "abused":
- Some viruses, for example, the Semliki forest virusSemliki Forest VirusThe Semliki Forest virus was first isolated from mosquitoes in the Semliki Forest, Uganda by the Uganda Virus Research Institute in 1942. It is known to cause disease in both animals and man...
, enter the cell through this mechanism. - CholeraCholeraCholera is an infection of the small intestine that is caused by the bacterium Vibrio cholerae. The main symptoms are profuse watery diarrhea and vomiting. Transmission occurs primarily by drinking or eating water or food that has been contaminated by the diarrhea of an infected person or the feces...
, diphtheriaDiphtheriaDiphtheria is an upper respiratory tract illness caused by Corynebacterium diphtheriae, a facultative anaerobic, Gram-positive bacterium. It is characterized by sore throat, low fever, and an adherent membrane on the tonsils, pharynx, and/or nasal cavity...
, anthraxAnthrax toxinAnthrax toxin is a three-protein exotoxin secreted by virulent strains of the bacterium, Bacillus anthracis--the causative agent of anthrax. The toxin was first discovered by Harry Smith in 1954. Anthrax toxin is composed of a cell-binding protein, known as protective antigen , and two enzyme...
, tetanusTetanusTetanus is a medical condition characterized by a prolonged contraction of skeletal muscle fibers. The primary symptoms are caused by tetanospasmin, a neurotoxin produced by the Gram-positive, rod-shaped, obligate anaerobic bacterium Clostridium tetani...
, botulinum, and other bacterial toxins enter the cell this way.
Protein destruction
Defective proteins are occasionally produced, or they may be damaged later, for example, by oxidative stress. Damaged proteins can be recycled. Proteins can have very different half lifes, mainly depending on their N-terminal amino acid residue. The recycling mechanism is mediated by ubiquitinUbiquitin
Ubiquitin is a small regulatory protein that has been found in almost all tissues of eukaryotic organisms. Among other functions, it directs protein recycling.Ubiquitin can be attached to proteins and label them for destruction...
.
Protein targeting in bacteria
With some exceptions, Bacteria lack membrane-bound organelles as found in eukaryotes, but they may assemble proteins onto various types of inclusions such as gas vesicles and storage granules. Bacteria may have a single plasma membrane (Gram-positive bacteria), or an inner membrane plus an outer membrane separated by the periplasm (Gram-negative bacteria). Proteins may be incorporated into the plasma membrane, or either trapped in the periplasm or secreted into the environment, according to whether or not there is an outer membrane. The basic mechanism at the plasma membrane is similar to the eukaryotic one. In addition, bacteria may target proteins into or across the outer membrane. Systems for secreting proteins across the bacterial outer membrane may be quite complex and play key roles in pathogenesis. These systems may be described as type I secretion, type II secretion, etc.In most Gram-positive bacteria, certain proteins are targeted for export across the plasma membrane and subsequent covalent attachment to the bacterial cell wall. A specialized enzyme, sortase
Sortase
Sortase refers to a group of prokaryotic enzymes which catalyze the assembly of pilins into pili, and the anchoring of pili to the cell wall. They act as both proteases and transpeptidases. Sortase, a transpeptidase present in almost all Gram-positive bacteria, anchors a range of important...
, cleaves the target protein at a characteristic recognition site near the protein C-terminus, such as an LPXTG motif (where X can be any amino acid), then transfers the protein onto the cell wall. An system analogous to sortase/LPXTG, termed exosortase/PEP-CTERM, is proposed to exist in a broad range of Gram-negative bacteria.
Secretory pathways
The secretory pathwaySecretory pathway
The secretory pathway is a series of steps a cell uses to move proteins out of the cell; a process known as secretion. The path of a protein destined for secretion has its origins in the rough endoplasmic reticulum, a membrane-bound compartment in the cell...
includes vesicular traffic, secretion, and endocytosis. Secretory protein
Secretory protein
A secretory protein is any protein, whether it be endocrine or exocrine, which is secreted by a cell. Secretory proteins include many hormones, enzymes, toxins, and antimicrobial peptides.Secretory proteins are synthesized in endoplasmic reticulum....
s follow this pathway.
Early stages
Retrograde transport is common in the early stages. Proteins that have been successfully delivered to the Golgi apparatusGolgi apparatus
The Golgi apparatus is an organelle found in most eukaryotic cells. It was identified in 1898 by the Italian physician Camillo Golgi, after whom the Golgi apparatus is named....
advance through cisternal progression.
Identifying protein targeting motifs in proteins
Minimotif MinerMinimotif Miner
Minimotif Miner is a program and database designed to identify minimotifs in any protein. Minimotifs are short contiguous peptide sequences that are known to have a function in at least one protein. Minimotifs are also called sequence motifs or short linear motifs or SLiMs. These are generally...
is a bioinformatics tool that searches protein sequence queries for a known protein targeting sequence motifs.