Gap-43 protein

GAP43
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 4E53
Identifiers
Aliases	GAP43, B-50, PP46, growth associated protein 43, GAP-43
External IDs	OMIM: 162060 MGI: 95639 HomoloGene: 1545 GeneCards: GAP43
Gene location (Human) Chr. Chromosome 3 (human)[1] Band 3q13.31 Start 115,623,510 bp[1] End 115,721,490 bp[1]
Gene location (Mouse) Chr. Chromosome 16 (mouse)[2] Band 16 B4|16 28.37 cM Start 42,068,805 bp[2] End 42,161,014 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in Brodmann area 10 frontal pole Brodmann area 23 dorsolateral prefrontal cortex superior frontal gyrus orbitofrontal cortex Brodmann area 9 cingulate gyrus parietal lobe temporal lobe Top expressed in superior cervical ganglion ventromedial nucleus ventral tegmental area lateral hypothalamus paraventricular nucleus of hypothalamus dorsomedial hypothalamic nucleus arcuate nucleus dorsal tegmental nucleus subiculum medial dorsal nucleus More reference expression data BioGPS More reference expression data
Gene ontology Molecular function lysophosphatidic acid binding phosphatidylinositol phosphate binding phosphatidylserine binding calmodulin binding protein binding Cellular component cytoplasm cell projection membrane postsynaptic density growth cone membrane synapse axon cell junction cell periphery filopodium membrane plasma membrane GABA-ergic synapse Biological process regulation of filopodium assembly cell differentiation cell fate commitment tissue regeneration glial cell differentiation nervous system development multicellular organism development protein kinase C-activating G protein-coupled receptor signaling pathway response to wounding regulation of growth axon choice point recognition axon development axon guidance regulation of postsynaptic specialization assembly axon regeneration Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2596 14432 Ensembl ENSG00000172020 ENSMUSG00000047261 UniProt P17677 P06837 RefSeq (mRNA) NM_002045 NM_001130064 NM_008083 RefSeq (protein) NP_001123536 NP_002036 NP_032109 Location (UCSC) Chr 3: 115.62 – 115.72 Mb Chr 16: 42.07 – 42.16 Mb PubMed search [3] [4]
Wikidata
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Growth Associated Protein 43 (GAP43) is a protein encoded by the GAP43 gene^[5] in humans.

GAP43 is called a "growth" or "plasticity" protein because it is expressed at high levels in neuronal growth cones during development^[6] and axonal regeneration, and it is phosphorylated after long-term potentiation and after learning.^{[citation needed]}

GAP43 is a crucial component of the axon and presynaptic terminal. Its null mutation leads to death within days after birth, due to axon pathfinding defects.^[7]

Synonyms

GAP43 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

GAP43, is a nervous tissue-specific cytoplasmic protein that can be attached to the membrane via a dual palmitoylation sequence on cysteines 3 and 4. This sequence targets GAP43 to lipid rafts. It is a major protein kinase C (PKC) substrate and is considered to play a key role in neurite formation, regeneration, and plasticity.^[8][9] 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.^[10]

Several different laboratories studying the same protein, now called GAP43, initially used different names. It was designated F1, then B-50, then GAP43, pp46, and finally neuromodulin, each name reflecting a different function of the same molecule.^[11] 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 grooming 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.

GAP43, the consensus choice for its designation,^[11] is a nervous system-specific protein that is attached to the membrane via a dual palmitoylation sequence on cysteines 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.^[8]

Because of the association and potential binding of GAP43 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 GAP43 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.

Clinical significance

Humans with a deletion in one allele of the GAP43 gene fail to form telencephalic commissures and are intellectually disabled.^[12][13]

References

Further reading

External links

• Gap-43+protein at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• ihop-net, Growth associated protein 43
• NCBI