ID   NEUM_MOUSE              Reviewed;         227 AA.
AC   P06837;
DT   01-JAN-1988, integrated into UniProtKB/Swiss-Prot.
DT   01-JAN-1988, sequence version 1.
DT   24-JAN-2024, entry version 195.
DE   RecName: Full=Neuromodulin;
DE   AltName: Full=Axonal membrane protein GAP-43;
DE   AltName: Full=Calmodulin-binding protein P-57;
DE   AltName: Full=Growth-associated protein 43;
GN   Name=Gap43; Synonyms=Basp2;
OS   Mus musculus (Mouse).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Mus; Mus.
OX   NCBI_TaxID=10090;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RX   PubMed=2442159; DOI=10.1016/s0021-9258(18)45330-6;
RA   Cimler B.M., Giebelhaus D.H., Wakim B.T., Storm D.R., Moon R.T.;
RT   "Characterization of murine cDNAs encoding P-57, a neural-specific
RT   calmodulin-binding protein.";
RL   J. Biol. Chem. 262:12158-12163(1987).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC   STRAIN=C57BL/6J; TISSUE=Retina;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [3]
RP   PROTEIN SEQUENCE OF 84-104, AND IDENTIFICATION BY MASS SPECTROMETRY.
RC   STRAIN=OF1; TISSUE=Hippocampus;
RA   Lubec G., Sunyer B., Chen W.-Q.;
RL   Submitted (JAN-2009) to UniProtKB.
RN   [4]
RP   IDENTIFICATION IN A COMPLEX WITH NCAM1; CDH2; PLCG1; FRS2; SRC; FGFR4 AND
RP   CTTN.
RX   PubMed=11433297; DOI=10.1038/35083041;
RA   Cavallaro U., Niedermeyer J., Fuxa M., Christofori G.;
RT   "N-CAM modulates tumour-cell adhesion to matrix by inducing FGF-receptor
RT   signalling.";
RL   Nat. Cell Biol. 3:650-657(2001).
RN   [5]
RP   TISSUE SPECIFICITY.
RX   PubMed=11573004; DOI=10.1073/pnas.191388398;
RA   Quattrone A., Pascale A., Nogues X., Zhao W., Gusev P., Pacini A.,
RA   Alkon D.L.;
RT   "Posttranscriptional regulation of gene expression in learning by the
RT   neuronal ELAV-like mRNA-stabilizing proteins.";
RL   Proc. Natl. Acad. Sci. U.S.A. 98:11668-11673(2001).
RN   [6]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Embryonic brain;
RX   PubMed=15345747; DOI=10.1074/mcp.m400085-mcp200;
RA   Ballif B.A., Villen J., Beausoleil S.A., Schwartz D., Gygi S.P.;
RT   "Phosphoproteomic analysis of the developing mouse brain.";
RL   Mol. Cell. Proteomics 3:1093-1101(2004).
RN   [7]
RP   IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain;
RX   PubMed=16452087; DOI=10.1074/mcp.t500041-mcp200;
RA   Trinidad J.C., Specht C.G., Thalhammer A., Schoepfer R., Burlingame A.L.;
RT   "Comprehensive identification of phosphorylation sites in postsynaptic
RT   density preparations.";
RL   Mol. Cell. Proteomics 5:914-922(2006).
RN   [8]
RP   INTERACTION WITH CALMODULIN, TISSUE SPECIFICITY, AND PHOSPHORYLATION.
RX   PubMed=18493953; DOI=10.1002/hipo.20442;
RA   Tanner D.C., Qiu S., Bolognani F., Partridge L.D., Weeber E.J.,
RA   Perrone-Bizzozero N.I.;
RT   "Alterations in mossy fiber physiology and GAP-43 expression and function
RT   in transgenic mice overexpressing HuD.";
RL   Hippocampus 18:814-823(2008).
RN   [9]
RP   PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-86; SER-96; THR-138; SER-142;
RP   SER-144; SER-145 AND THR-172, AND IDENTIFICATION BY MASS SPECTROMETRY
RP   [LARGE SCALE ANALYSIS].
RC   TISSUE=Brain, Brown adipose tissue, Heart, and Lung;
RX   PubMed=21183079; DOI=10.1016/j.cell.2010.12.001;
RA   Huttlin E.L., Jedrychowski M.P., Elias J.E., Goswami T., Rad R.,
RA   Beausoleil S.A., Villen J., Haas W., Sowa M.E., Gygi S.P.;
RT   "A tissue-specific atlas of mouse protein phosphorylation and expression.";
RL   Cell 143:1174-1189(2010).
RN   [10]
RP   PALMITOYLATION AT CYS-3 AND CYS-4, AND MUTAGENESIS OF CYS-3 AND CYS-4.
RX   PubMed=27875292; DOI=10.1074/jbc.m116.732768;
RA   Kilpatrick C.L., Murakami S., Feng M., Wu X., Lal R., Chen G., Du K.,
RA   Luscher B.;
RT   "Dissociation of Golgi-associated DHHC-type Zinc Finger Protein (GODZ)- and
RT   Sertoli Cell Gene with a Zinc Finger Domain-beta (SERZ-beta)-mediated
RT   Palmitoylation by Loss of Function Analyses in Knock-out Mice.";
RL   J. Biol. Chem. 291:27371-27386(2016).
RN   [11]
RP   TISSUE SPECIFICITY, AND INDUCTION BY NERVE INJURY.
RX   PubMed=28111162; DOI=10.1016/j.brainres.2017.01.019;
RA   Sanna M.D., Ghelardini C., Galeotti N.;
RT   "HuD-mediated distinct BDNF regulatory pathways promote regeneration after
RT   nerve injury.";
RL   Brain Res. 1659:55-63(2017).
CC   -!- FUNCTION: This protein is associated with nerve growth. It is a major
CC       component of the motile 'growth cones' that form the tips of elongating
CC       axons. Plays a role in axonal and dendritic filopodia induction.
CC       {ECO:0000250|UniProtKB:P17677}.
CC   -!- SUBUNIT: Identified in a complex containing FGFR4, NCAM1, CDH2, PLCG1,
CC       FRS2, SRC, SHC1, GAP43 and CTTN (PubMed:11433297). Interacts (via IQ
CC       domain) with calmodulin (PubMed:18493953). Binds calmodulin with a
CC       greater affinity in the absence of Ca(2+) than in its presence (By
CC       similarity). {ECO:0000250|UniProtKB:P06836,
CC       ECO:0000269|PubMed:11433297, ECO:0000269|PubMed:18493953}.
CC   -!- SUBCELLULAR LOCATION: Cell membrane {ECO:0000250|UniProtKB:P17677};
CC       Peripheral membrane protein {ECO:0000250|UniProtKB:P17677}; Cytoplasmic
CC       side {ECO:0000250|UniProtKB:P17677}. Cell projection, growth cone
CC       membrane {ECO:0000250|UniProtKB:P17677}; Peripheral membrane protein
CC       {ECO:0000250|UniProtKB:P17677}; Cytoplasmic side
CC       {ECO:0000250|UniProtKB:P17677}. Synapse {ECO:0000250|UniProtKB:P17677}.
CC       Cell projection, filopodium membrane {ECO:0000250|UniProtKB:P17677};
CC       Peripheral membrane protein {ECO:0000250|UniProtKB:P17677}. Perikaryon
CC       {ECO:0000250|UniProtKB:P07936}. Cell projection, dendrite
CC       {ECO:0000250|UniProtKB:P07936}. Cell projection, axon
CC       {ECO:0000250|UniProtKB:P07936}. Cytoplasm
CC       {ECO:0000250|UniProtKB:P07936}. Note=Cytoplasmic surface of growth cone
CC       and synaptic plasma membranes. {ECO:0000250|UniProtKB:P17677}.
CC   -!- TISSUE SPECIFICITY: Expressed in the hippocampus (at protein level)
CC       (PubMed:18493953, PubMed:11573004). Expressed in the dorsal root
CC       ganglion and the spinal cord (at protein level) (PubMed:28111162).
CC       {ECO:0000269|PubMed:11573004, ECO:0000269|PubMed:18493953,
CC       ECO:0000269|PubMed:28111162}.
CC   -!- INDUCTION: Up-regulated after memory training in radial arm maze
CC       experiments (PubMed:11573004). Up-regulated after sciatic nerve injury
CC       (PubMed:28111162). {ECO:0000269|PubMed:11573004,
CC       ECO:0000269|PubMed:28111162}.
CC   -!- PTM: Phosphorylated (PubMed:18493953). Phosphorylation of this protein
CC       by a protein kinase C is specifically correlated with certain forms of
CC       synaptic plasticity (By similarity). {ECO:0000250|UniProtKB:P07936,
CC       ECO:0000269|PubMed:18493953}.
CC   -!- PTM: Palmitoylated by ZDHHC3 (PubMed:27875292). Palmitoylation is
CC       regulated by ARF6 and is essential for plasma membrane association and
CC       axonal and dendritic filopodia induction. Deacylated by LYPLA2 (By
CC       similarity). {ECO:0000250|UniProtKB:P17677,
CC       ECO:0000269|PubMed:27875292}.
CC   -!- SIMILARITY: Belongs to the neuromodulin family. {ECO:0000305}.
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DR   EMBL; J02809; AAA37377.1; -; mRNA.
DR   EMBL; BC028288; AAH28288.1; -; mRNA.
DR   EMBL; BC080758; AAH80758.1; -; mRNA.
DR   CCDS; CCDS28177.1; -.
DR   PIR; A29800; A29800.
DR   RefSeq; NP_032109.1; NM_008083.2.
DR   PDB; 4E53; X-ray; 2.69 A; A/B=34-57.
DR   PDBsum; 4E53; -.
DR   AlphaFoldDB; P06837; -.
DR   SMR; P06837; -.
DR   BioGRID; 199828; 8.
DR   CORUM; P06837; -.
DR   IntAct; P06837; 3.
DR   MINT; P06837; -.
DR   STRING; 10090.ENSMUSP00000099881; -.
DR   GlyGen; P06837; 2 sites, 1 O-linked glycan (2 sites).
DR   iPTMnet; P06837; -.
DR   PhosphoSitePlus; P06837; -.
DR   SwissPalm; P06837; -.
DR   MaxQB; P06837; -.
DR   PaxDb; 10090-ENSMUSP00000099881; -.
DR   PeptideAtlas; P06837; -.
DR   ProteomicsDB; 252953; -.
DR   Antibodypedia; 2805; 1009 antibodies from 43 providers.
DR   DNASU; 14432; -.
DR   Ensembl; ENSMUST00000102817.5; ENSMUSP00000099881.5; ENSMUSG00000047261.10.
DR   GeneID; 14432; -.
DR   KEGG; mmu:14432; -.
DR   UCSC; uc007zfv.1; mouse.
DR   AGR; MGI:95639; -.
DR   CTD; 2596; -.
DR   MGI; MGI:95639; Gap43.
DR   VEuPathDB; HostDB:ENSMUSG00000047261; -.
DR   eggNOG; ENOG502RXWF; Eukaryota.
DR   GeneTree; ENSGT00730000111265; -.
DR   HOGENOM; CLU_102989_0_0_1; -.
DR   InParanoid; P06837; -.
DR   OMA; PNQTNDK; -.
DR   OrthoDB; 4371674at2759; -.
DR   PhylomeDB; P06837; -.
DR   TreeFam; TF333213; -.
DR   Reactome; R-MMU-373760; L1CAM interactions.
DR   BioGRID-ORCS; 14432; 1 hit in 79 CRISPR screens.
DR   ChiTaRS; Gap43; mouse.
DR   PRO; PR:P06837; -.
DR   Proteomes; UP000000589; Chromosome 16.
DR   RNAct; P06837; Protein.
DR   Bgee; ENSMUSG00000047261; Expressed in embryonic brain and 229 other cell types or tissues.
DR   GO; GO:0030424; C:axon; IDA:MGI.
DR   GO; GO:0071944; C:cell periphery; IDA:MGI.
DR   GO; GO:0005737; C:cytoplasm; IDA:MGI.
DR   GO; GO:0030425; C:dendrite; IEA:UniProtKB-SubCell.
DR   GO; GO:0031527; C:filopodium membrane; ISO:MGI.
DR   GO; GO:0098982; C:GABA-ergic synapse; ISO:MGI.
DR   GO; GO:0032584; C:growth cone membrane; IEA:UniProtKB-SubCell.
DR   GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR   GO; GO:0005886; C:plasma membrane; IDA:MGI.
DR   GO; GO:0014069; C:postsynaptic density; IDA:MGI.
DR   GO; GO:0098793; C:presynapse; ISO:MGI.
DR   GO; GO:0005516; F:calmodulin binding; IBA:GO_Central.
DR   GO; GO:0035727; F:lysophosphatidic acid binding; ISO:MGI.
DR   GO; GO:1901981; F:phosphatidylinositol phosphate binding; ISO:MGI.
DR   GO; GO:0001786; F:phosphatidylserine binding; ISO:MGI.
DR   GO; GO:0048708; P:astrocyte differentiation; IMP:MGI.
DR   GO; GO:0016198; P:axon choice point recognition; IMP:MGI.
DR   GO; GO:0007411; P:axon guidance; IMP:MGI.
DR   GO; GO:0031103; P:axon regeneration; IBA:GO_Central.
DR   GO; GO:0045165; P:cell fate commitment; IMP:MGI.
DR   GO; GO:0060019; P:radial glial cell differentiation; IMP:MGI.
DR   GO; GO:0051489; P:regulation of filopodium assembly; ISO:MGI.
DR   GO; GO:0040008; P:regulation of growth; IEA:InterPro.
DR   GO; GO:0099150; P:regulation of postsynaptic specialization assembly; ISO:MGI.
DR   GO; GO:0042246; P:tissue regeneration; IBA:GO_Central.
DR   Gene3D; 1.20.5.190; -; 1.
DR   InterPro; IPR000048; IQ_motif_EF-hand-BS.
DR   InterPro; IPR001422; Neuromodulin.
DR   InterPro; IPR017454; Neuromodulin_C.
DR   InterPro; IPR018947; Neuromodulin_gap-junction_N.
DR   InterPro; IPR033137; Neuromodulin_P_site.
DR   InterPro; IPR018243; Neuromodulin_palmitoyl_site.
DR   PANTHER; PTHR10699; NEUROMODULIN; 1.
DR   PANTHER; PTHR10699:SF15; NEUROMODULIN; 1.
DR   Pfam; PF00612; IQ; 1.
DR   Pfam; PF06614; Neuromodulin; 1.
DR   Pfam; PF10580; Neuromodulin_N; 1.
DR   PRINTS; PR00215; NEUROMODULIN.
DR   SMART; SM00015; IQ; 1.
DR   PROSITE; PS50096; IQ; 1.
DR   PROSITE; PS00412; NEUROMODULIN_1; 1.
DR   PROSITE; PS00413; NEUROMODULIN_2; 1.
DR   Genevisible; P06837; MM.
PE   1: Evidence at protein level;
KW   3D-structure; Calmodulin-binding; Cell membrane; Cell projection;
KW   Cytoplasm; Developmental protein; Differentiation;
KW   Direct protein sequencing; Growth regulation; Lipoprotein; Membrane;
KW   Neurogenesis; Palmitate; Phosphoprotein; Reference proteome; Synapse.
FT   CHAIN           1..227
FT                   /note="Neuromodulin"
FT                   /id="PRO_0000159597"
FT   DOMAIN          31..60
FT                   /note="IQ"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00116"
FT   REGION          1..227
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        8..36
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        51..86
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        104..125
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        132..146
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        192..227
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         41
FT                   /note="Phosphoserine; by PHK"
FT                   /evidence="ECO:0000250|UniProtKB:P06836, ECO:0000305"
FT   MOD_RES         86
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         96
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         138
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         142
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         144
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         145
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         172
FT                   /note="Phosphothreonine"
FT                   /evidence="ECO:0007744|PubMed:21183079"
FT   MOD_RES         192
FT                   /note="Phosphoserine; by CK2"
FT                   /evidence="ECO:0000250|UniProtKB:P06836"
FT   MOD_RES         193
FT                   /note="Phosphoserine; by CK2"
FT                   /evidence="ECO:0000250|UniProtKB:P06836"
FT   LIPID           3
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000305|PubMed:27875292"
FT   LIPID           4
FT                   /note="S-palmitoyl cysteine"
FT                   /evidence="ECO:0000305|PubMed:27875292"
FT   MUTAGEN         3
FT                   /note="C->S: Loss of palmitoylation; when associated with
FT                   S-4."
FT                   /evidence="ECO:0000269|PubMed:27875292"
FT   MUTAGEN         4
FT                   /note="C->S: Loss of palmitoylation; when associated with
FT                   S-3."
FT                   /evidence="ECO:0000269|PubMed:27875292"
FT   HELIX           35..51
FT                   /evidence="ECO:0007829|PDB:4E53"
SQ   SEQUENCE   227 AA;  23632 MW;  14803B2F8F0649F7 CRC64;
     MLCCMRRTKQ VEKNDEDQKI EQDGVKPEDK AHKAATKIQA SFRGHITRKK LKGEKKGDAP
     AAEAEAKEKD DAPVADGVEK KEGDGSATTD AAPATSPKAE EPSKAGDAPS EEKKGEGDAA
     PSEEKAGSAE TESAAKATTD NSPSSKAEDG PAKEEPKQAD VPAAVTDAAA TTPAAEDAAT
     KAAQPPTETA ESSQAEEEKD AVDEAKPKES ARQDEGKEDP EADQEHA
//