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Gap-43 protein

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(Redirected from Neuromodulin)
GAP43
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesGAP43, B-50, PP46, growth associated protein 43, GAP-43
External IDsOMIM: 162060; MGI: 95639; HomoloGene: 1545; GeneCards: GAP43; OMA:GAP43 - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 16: 42.07 – 42.16 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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

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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

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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

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

References

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  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000172020 – Ensembl, May 2017
  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000047261 – Ensembl, May 2017
  3. ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ^ Kosik KS, Orecchio LD, Bruns GA, Benowitz LI, MacDonald GP, Cox DR, Neve RL (Apr 1988). "Human GAP-43: its deduced amino acid sequence and chromosomal localization in mouse and human". Neuron. 1 (2): 127–32. doi:10.1016/0896-6273(88)90196-1. PMID 3272162. S2CID 12067138.
  6. ^ Referenced within : Rosskothen-Kuhl N, Illing RB (2014). "Gap43 Transcription Modulation in the Adult Brain Depends on Sensory Activity and Synaptic Cooperation". PLOS ONE. 9 (3): e92624. Bibcode:2014PLoSO...992624R. doi:10.1371/journal.pone.0092624. PMC 3960265. PMID 24647228.
  7. ^ "Entrez Gene: GAP43 growth associated protein 43".
  8. ^ a b Benowitz LI, Routtenberg A (Feb 1997). "GAP-43: an intrinsic determinant of neuronal development and plasticity". Trends in Neurosciences. 20 (2): 84–91. doi:10.1016/S0166-2236(96)10072-2. PMID 9023877. S2CID 35082372.
  9. ^ Aarts LH, Schotman P, Verhaagen J, Schrama LH, Gispen WH (1998). "The Role of the Neural Growth Associated Protein B-50/Gap-43 in Morphogenesis". Molecular and Cellular Mechanisms of Neuronal Plasticity. Advances in Experimental Medicine and Biology. Vol. 446. pp. 85–106. doi:10.1007/978-1-4615-4869-0_6. ISBN 978-1-4613-7209-7. PMID 10079839.
  10. ^ Mishra R, ManiS (2008). "GAP-43 is key to mitotic spindle control and centrosome-based polarization in neurons". Cell Cycle. 7 (3): 348–357. doi:10.4161/cc.7.3.5235. PMID 18235238.
  11. ^ a b Benowitz LI, Routtenberg A (1987). "A membrane phosphoprotein associated with neural development, axonal regeneration, phospholipid metabolism, and synaptic plasticity". Trends in Neurosciences. 10 (12): 527–532. doi:10.1016/0166-2236(87)90135-4. S2CID 54322365.
  12. ^ Genuardi M, Calvieri F, Tozzi C, Coslovi R, Neri G (Oct 1994). "A new case of interstitial deletion of chromosome 3q, del(3q)(q13.12q21.3), with agenesis of the corpus callosum". Clinical Dysmorphology. 3 (4): 292–6. doi:10.1097/00019605-199410000-00003. PMID 7894733. S2CID 38716384.
  13. ^ Mackie Ogilvie C, Rooney SC, Hodgson SV, Berry AC (Mar 1998). "Deletion of chromosome 3q proximal region gives rise to a variable phenotype". Clinical Genetics. 53 (3): 220–2. doi:10.1111/j.1399-0004.1998.tb02681.x. PMID 9630079. S2CID 20499346.

Further reading

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