ID   FRE2D_DISSA             Reviewed;          14 AA.
AC   P0DTV5;
DT   17-JUN-2020, integrated into UniProtKB/Swiss-Prot.
DT   17-JUN-2020, sequence version 1.
DT   25-MAY-2022, entry version 3.
DE   RecName: Full=Frenatin-2D {ECO:0000303|PubMed:23262358};
DE   AltName: Full=Host-defense peptide {ECO:0000303|PubMed:23262358};
OS   Discoglossus sardus (Tyrrhenian painted frog).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Amphibia;
OC   Batrachia; Anura; Alytidae; Discoglossinae; Discoglossus.
OX   NCBI_TaxID=191474;
RN   [1]
RP   PROTEIN SEQUENCE, FUNCTION, SUBCELLULAR LOCATION, SYNTHESIS, MASS
RP   SPECTROMETRY, AND AMIDATION AT ILE-14.
RC   TISSUE=Skin secretion;
RX   PubMed=23262358; DOI=10.1016/j.peptides.2012.12.012;
RA   Conlon J.M., Mechkarska M., Pantic J.M., Lukic M.L., Coquet L.,
RA   Leprince J., Nielsen P.F., Rinaldi A.C.;
RT   "An immunomodulatory peptide related to frenatin 2 from skin secretions of
RT   the Tyrrhenian painted frog Discoglossus sardus (Alytidae).";
RL   Peptides 40:65-71(2013).
RN   [2]
RP   FUNCTION, SYNTHESIS, AND MUTAGENESIS OF ASP-1; THR-5; GLY-7; ASN-8; PRO-10;
RP   12-PRO-PHE-13 AND ILE-14.
RX   PubMed=30244134; DOI=10.1016/j.biochi.2018.09.008;
RA   Musale V., Guilhaudis L., Abdel-Wahab Y.H.A., Flatt P.R., Conlon J.M.;
RT   "Insulinotropic activity of the host-defense peptide frenatin 2D:
RT   conformational, structure-function and mechanistic studies.";
RL   Biochimie 156:12-21(2019).
CC   -!- FUNCTION: Peptide with unknown biological function that may act on skin
CC       macrophages to produce a cytokine-mediated stimulation of the adaptive
CC       immune system in response to invasion by microorganisms
CC       (PubMed:23262358). It does not show antimicrobial and hemolytic
CC       activities but stimulates production of the pro-inflammatory cytokines
CC       TNF-alpha and IL-1beta by mouse peritoneal macrophages and does not
CC       potentiate the stimulation produced by lipopolysaccharide (LPS)
CC       (PubMed:23262358). The peptide increases IL-12 production in both
CC       unstimulated and LPS-stimulated cells, but it does not stimulate IL-6
CC       production in a significant manner (PubMed:23262358). Stimulates
CC       insulin release from pancreatic beta-cells in a dose-dependent manner
CC       (PubMed:30244134). This insulinotropic activity is relatively weak
CC       compared to that of GLP-1 (PubMed:30244134). Acts without effects on
CC       membrane depolarization or changes in calcium current
CC       (PubMed:30244134). Insulin release is predominantly mediated by the
CC       K(ATP) channel-independent pathway (PubMed:30244134). Like GLP-1, but
CC       in a less potent manner, this peptide stimulates beta-cell
CC       proliferation (PubMed:30244134). In a comparable potency to that
CC       provided by GLP-1, also provides protection of cells against cytokine-
CC       induced apoptosis (PubMed:30244134). {ECO:0000269|PubMed:23262358,
CC       ECO:0000269|PubMed:30244134}.
CC   -!- SUBCELLULAR LOCATION: Secreted {ECO:0000269|PubMed:23262358}.
CC   -!- TISSUE SPECIFICITY: Expressed by the skin glands.
CC       {ECO:0000305|PubMed:23262358}.
CC   -!- PTM: Ile-14 amidation is not necessary for insulin release stimulation,
CC       since the synthetic non-amidated peptide shows the same activity as the
CC       amidated peptide. {ECO:0000269|PubMed:30244134}.
CC   -!- MASS SPECTROMETRY: Mass=1481.9; Method=MALDI;
CC       Evidence={ECO:0000269|PubMed:23262358};
CC   -!- SIMILARITY: Belongs to the frog skin active peptide (FSAP) family.
CC       Frenatin subfamily. {ECO:0000305}.
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DR   GO; GO:0005576; C:extracellular region; IEA:UniProtKB-SubCell.
DR   GO; GO:0045087; P:innate immune response; IEA:UniProtKB-KW.
PE   1: Evidence at protein level;
KW   Amidation; Amphibian defense peptide; Direct protein sequencing; Immunity;
KW   Innate immunity; Secreted.
FT   PEPTIDE         1..14
FT                   /note="Frenatin-2D"
FT                   /evidence="ECO:0000269|PubMed:23262358"
FT                   /id="PRO_0000450236"
FT   MOD_RES         14
FT                   /note="Isoleucine amide"
FT                   /evidence="ECO:0000269|PubMed:23262358"
FT   MUTAGEN         1
FT                   /note="D->W: No change in insulin-release stimulation."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         5
FT                   /note="T->W: Loss of insulin-release stimulation (>30,000-
FT                   fold)."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         7
FT                   /note="G->W: No change in insulin-release stimulation."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         8
FT                   /note="N->W: Loss of insulin-release stimulation (>30,000-
FT                   fold)."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         10
FT                   /note="P->W: Loss of insulin-release stimulation (>30,000-
FT                   fold)."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         12..13
FT                   /note="PF->FP: Loss of insulin-release stimulation
FT                   (>30,000-fold)."
FT                   /evidence="ECO:0000269|PubMed:30244134"
FT   MUTAGEN         14
FT                   /note="I->W: Loss of insulin-release stimulation (>30,000-
FT                   fold)."
FT                   /evidence="ECO:0000269|PubMed:30244134"
SQ   SEQUENCE   14 AA;  1483 MW;  256584A2154F7048 CRC64;
     DLLGTLGNLP LPFI