Gap-43 protein
Encyclopedia
Growth Associated Protein 43 also known as Gap43 is a protein
that in humans is encoded by the GAP43 gene
.
Gap43 has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development
, during axonal regeneration and is phosphorylated
after long-term potentiation
(LTP) and after learning. This protein is considered a crucial component of the axon and presynaptic
terminal, its null mutation leading to death within days after birth due to axon pathfinding defects.
ic protein that can be attached to the membrane
via a dual palmitoylation
sequence on cysteine
s 3 and 4. This sequence targets GAP-43 to lipid raft
s. It is a major protein kinase C (PKC
) substrate and is considered to play a key role in neurite
formation, regeneration, and plasticity. The role of GAP-43 in CNS development is not limited to effects on axons: It is also a component of the centrosome
, and differentiating neurons that do not express GAP-43 show mislocalization of the centrosome and mitotic spindles, particularly in neurogenic cell divisions. As a consequence, in the cerebellum
, the neuronal precursor pool fails to expand normally and the cerebellum is significantly smaller. GAP-43 deletion
is lethal days after birth which demonstrates that GAP-43 plays a critical role in the development of the mammalian CNS.
Several different laboratories studying the same protein, now called GAP-43, initially used different names. It was designated F1, then B-50, then GAP-43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule. F1 was localized to synapses, and was increased in its phosphorylation one day after learning. However, F1 was not cAMP kinase dependent. B-50 was regulated by the pituitary peptide ACTH and was associated with the grooming of behavior. In the case of GAP-43, it was designated as a growth-associated protein because its synthesis was upregulated during axonal regeneration. Pp46 was concentrated in neuronal growth cones and was thus postulated to play an important role in brain development. In the case of neuromodulin, it was shown to bind calmodulin
avidly.
GAP-43, the consensus choice for its designation is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation
sequence on cysteine
s 3 and 4, though it can exist in the non-bound form in the cytoplasm
. This dual sequence enables the association of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] or PIP2, with actin
, facilitating the latter’s polymerization thereby regulating neuronal structure. This can occur within a lipid raft so as to compartmentalize and localize motility of filopodia in growth cones in developing brains, and could also remodel presynaptic terminals in adults in an activity-dependent manner. GAP-43 is also a protein kinase C (PKC) substrate. Phosphorylation of serine-41 on GAP-43 by PKC regulates neurite formation, regeneration, and synaptic plasticity.
Because of the association and potential binding of GAP-43 with a number of different molecules, including PKC, PIP2, actin
, calmodulin
, spectrin
, palmitate, synaptophysin
, amyloid
and tau protein
, it may be useful to think of GAP-43 as an adaptor protein situated within the terminal in a supramolecular complex regulating presynaptic terminal functions, particularly bidirectional communication with the postsynaptic process. Its important role in memory and information storage is executed through its cell biological mechanisms of phosphorylation, palmitoylation
, protein-protein interaction and structural remodeling via actin
polymerization.
of the GAP-43 gene fail to form telencephalic commissures and are mentally retarded,. Mice in which GAP-43 has been genetically deleted show profound errors in axon targeting in the CNS: telencephalic commissures fail to form, thalamocortical afferents are mistargeted, especially in somatosensory, particularly barrel, cortex. GAP-43 is not only important for axon targeting during development but it has been shown to be important also for the maintenance of the structure of axonal fibres and of their synaptic terminals in wild-type rodents both during normal conditions and during lesion-induced axonal sprouting. The cerebellum is also affected. GAP-43 is also haploinsufficient
for the cortical phenotypes and the severity of the axon targeting phenotype
is directly related to the extent to which the affected axons are phosphorylated by PKC
, suggesting that axons require a functional threshold of phosphorylated GAP-43 for targeting to occur normally. Moreover, elevation above this threshold in GAP-43 mice can enhance learning and also facilitate a physiological model of learning, long-term potentiation (LTP). However, further enrichment beyond a certain level can be devastating to cognitive functions.
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...
that in humans is encoded by the GAP43 gene
Gene
A gene is a molecular unit of heredity of a living organism. It is a name given to some stretches of DNA and RNA that code for a type of protein or for an RNA chain that has a function in the organism. Living beings depend on genes, as they specify all proteins and functional RNA chains...
.
Gap43 has been termed a 'growth' or 'plasticity' protein because it is expressed at high levels in neuronal growth cones during development
Morphogenesis
Morphogenesis , is the biological process that causes an organism to develop its shape...
, during axonal regeneration and is phosphorylated
Phosphorylation
Phosphorylation is the addition of a phosphate group to a protein or other organic molecule. Phosphorylation activates or deactivates many protein enzymes....
after long-term potentiation
Long-term potentiation
In neuroscience, long-term potentiation is a long-lasting enhancement in signal transmission between two neurons that results from stimulating them synchronously. It is one of several phenomena underlying synaptic plasticity, the ability of chemical synapses to change their strength...
(LTP) and after learning. This protein is considered a crucial component of the axon and presynaptic
Chemical synapse
Chemical synapses are specialized junctions through which neurons signal to each other and to non-neuronal cells such as those in muscles or glands. Chemical synapses allow neurons to form circuits within the central nervous system. They are crucial to the biological computations that underlie...
terminal, its null mutation leading to death within days after birth due to axon pathfinding defects.
Synonyms
Gap-43 is also referred to as:- protein F1
- neuromodulin
- neural phosphoprotein B-50
- axonal membrane protein GAP-43
- calmodulin-binding protein P-57
- nerve growth-related peptide GAP43
- neuron growth-associated protein 43
Function
GAP-43, is a nervous tissue-specific cytoplasmCytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
ic protein that can be attached to the 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...
via a dual palmitoylation
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
sequence on cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s 3 and 4. This sequence targets GAP-43 to lipid raft
Lipid raft
The plasma membrane of cells is made of a combination of glycosphingolipids and protein receptors organized in glycolipoprotein microdomains termed lipid rafts...
s. It is a major protein kinase C (PKC
Protein kinase C
Protein 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...
) substrate and is considered to play a key role in neurite
Neurite
A neurite refers to any projection from the cell body of a neuron. This projection can be either an axon or a dendrite. The term is frequently used when speaking of immature or developing neurons, especially of cells in culture, because it can be difficult to tell axons from dendrites before...
formation, regeneration, and plasticity. The role of GAP-43 in CNS development is not limited to effects on axons: It is also a component of the centrosome
Centrosome
In cell biology, the centrosome is an organelle that serves as the main microtubule organizing center of the animal cell as well as a regulator of cell-cycle progression. It was discovered by Edouard Van Beneden in 1883...
, and differentiating neurons that do not express GAP-43 show mislocalization of the centrosome and mitotic spindles, particularly in neurogenic cell divisions. As a consequence, in the cerebellum
Cerebellum
The cerebellum is a region of the brain that plays an important role in motor control. It may also be involved in some cognitive functions such as attention and language, and in regulating fear and pleasure responses, but its movement-related functions are the most solidly established...
, the neuronal precursor pool fails to expand normally and the cerebellum is significantly smaller. GAP-43 deletion
Knockout mouse
A knockout mouse is a genetically engineered mouse in which researchers have inactivated, or "knocked out," an existing gene by replacing it or disrupting it with an artificial piece of DNA...
is lethal days after birth which demonstrates that GAP-43 plays a critical role in the development of the mammalian CNS.
Several different laboratories studying the same protein, now called GAP-43, initially used different names. It was designated F1, then B-50, then GAP-43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule. F1 was localized to synapses, and was increased in its phosphorylation one day after learning. However, F1 was not cAMP kinase dependent. B-50 was regulated by the pituitary peptide ACTH and was associated with the grooming of behavior. In the case of GAP-43, it was designated as a growth-associated protein because its synthesis was upregulated during axonal regeneration. Pp46 was concentrated in neuronal growth cones and was thus postulated to play an important role in brain development. In the case of neuromodulin, it was shown to bind calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
avidly.
GAP-43, the consensus choice for its designation is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
sequence on cysteine
Cysteine
Cysteine is an α-amino acid with the chemical formula HO2CCHCH2SH. It is a non-essential amino acid, which means that it is biosynthesized in humans. Its codons are UGU and UGC. The side chain on cysteine is thiol, which is polar and thus cysteine is usually classified as a hydrophilic amino acid...
s 3 and 4, though it can exist in the non-bound form in the cytoplasm
Cytoplasm
The cytoplasm is a small gel-like substance residing between the cell membrane holding all the cell's internal sub-structures , except for the nucleus. All the contents of the cells of prokaryote organisms are contained within the cytoplasm...
. This dual sequence enables the association of phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2] or PIP2, with actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
, facilitating the latter’s polymerization thereby regulating neuronal structure. This can occur within a lipid raft so as to compartmentalize and localize motility of filopodia in growth cones in developing brains, and could also remodel presynaptic terminals in adults in an activity-dependent manner. GAP-43 is also a protein kinase C (PKC) substrate. Phosphorylation of serine-41 on GAP-43 by PKC regulates neurite formation, regeneration, and synaptic plasticity.
Because of the association and potential binding of GAP-43 with a number of different molecules, including PKC, PIP2, actin
Actin
Actin is a globular, roughly 42-kDa moonlighting protein found in all eukaryotic cells where it may be present at concentrations of over 100 μM. It is also one of the most highly-conserved proteins, differing by no more than 20% in species as diverse as algae and humans...
, calmodulin
Calmodulin
Calmodulin is a calcium-binding protein expressed in all eukaryotic cells...
, spectrin
Spectrin
Spectrin is a cytoskeletal protein that lines the intracellular side of the plasma membrane of many cell types in pentagonal or hexagonal arrangements, forming a scaffolding and playing an important role in maintenance of plasma membrane integrity and cytoskeletal structure...
, palmitate, synaptophysin
Synaptophysin
Synaptophysin also known as the major synaptic vesicle protein p38 is a protein that in humans is encoded by the SYP gene.-Genomics:...
, amyloid
Amyloid
Amyloids are insoluble fibrous protein aggregates sharing specific structural traits. Abnormal accumulation of amyloid in organs may lead to amyloidosis, and may play a role in various neurodegenerative diseases.-Definition:...
and tau protein
Tau protein
Tau proteins are proteins that stabilize microtubules. They are abundant in neurons of the central nervous system and are less common elsewhere, but are also expressed at very low levels in CNS astrocytes and oligodendrocytes...
, it may be useful to think of GAP-43 as an adaptor protein situated within the terminal in a supramolecular complex regulating presynaptic terminal functions, particularly bidirectional communication with the postsynaptic process. Its important role in memory and information storage is executed through its cell biological mechanisms of phosphorylation, palmitoylation
Palmitoylation
S-Palmitoylation is the covalent attachment of fatty acids, such as palmitic acid, to cysteine residues of membrane proteins. The precise function of palmitoylation depends on the particular protein being considered. Palmitoylation enhances the hydrophobicity of proteins and contributes to their...
, protein-protein interaction and structural remodeling via actin
Actin remodeling of neurons
Actin remodeling is a biochemical process in cells. In the actin remodeling of neurons, the protein actin is part of the process to change the shape and structure of dendritic spines. G-actin is the monomer form of actin, and is uniformly distributed throughout the axon and the dendrite...
polymerization.
Clinical significance
Humans with a deletion in one alleleAllele
An allele is one of two or more forms of a gene or a genetic locus . "Allel" is an abbreviation of allelomorph. Sometimes, different alleles can result in different observable phenotypic traits, such as different pigmentation...
of the GAP-43 gene fail to form telencephalic commissures and are mentally retarded,. Mice in which GAP-43 has been genetically deleted show profound errors in axon targeting in the CNS: telencephalic commissures fail to form, thalamocortical afferents are mistargeted, especially in somatosensory, particularly barrel, cortex. GAP-43 is not only important for axon targeting during development but it has been shown to be important also for the maintenance of the structure of axonal fibres and of their synaptic terminals in wild-type rodents both during normal conditions and during lesion-induced axonal sprouting. The cerebellum is also affected. GAP-43 is also haploinsufficient
Haploinsufficiency
Haploinsufficiency occurs when a diploid organism only has a single functional copy of a gene and the single functional copy of the gene does not produce enough of a gene product to bring about a wild-type condition, leading to an abnormal or diseased state...
for the cortical phenotypes and the severity of the axon targeting phenotype
Phenotype
A phenotype is an organism's observable characteristics or traits: such as its morphology, development, biochemical or physiological properties, behavior, and products of behavior...
is directly related to the extent to which the affected axons are phosphorylated by PKC
Protein kinase C
Protein 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...
, suggesting that axons require a functional threshold of phosphorylated GAP-43 for targeting to occur normally. Moreover, elevation above this threshold in GAP-43 mice can enhance learning and also facilitate a physiological model of learning, long-term potentiation (LTP). However, further enrichment beyond a certain level can be devastating to cognitive functions.