ID   FKBP4_RABIT             Reviewed;         458 AA.
AC   P27124;
DT   01-AUG-1992, integrated into UniProtKB/Swiss-Prot.
DT   23-JAN-2007, sequence version 3.
DT   27-MAR-2024, entry version 183.
DE   RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4;
DE            Short=PPIase FKBP4;
DE            EC=5.2.1.8;
DE   AltName: Full=52 kDa FK506-binding protein;
DE            Short=52 kDa FKBP;
DE            Short=FKBP-52;
DE   AltName: Full=59 kDa immunophilin;
DE            Short=p59;
DE   AltName: Full=FK506-binding protein 4;
DE            Short=FKBP-4;
DE   AltName: Full=FKBP59;
DE   AltName: Full=HSP-binding immunophilin;
DE            Short=HBI;
DE   AltName: Full=Immunophilin FKBP52;
DE   AltName: Full=Rotamase;
DE   Contains:
DE     RecName: Full=Peptidyl-prolyl cis-trans isomerase FKBP4, N-terminally processed;
GN   Name=FKBP4; Synonyms=P59;
OS   Oryctolagus cuniculus (Rabbit).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Lagomorpha; Leporidae; Oryctolagus.
OX   NCBI_TaxID=9986;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA].
RC   TISSUE=Liver;
RX   PubMed=1537818; DOI=10.1016/s0021-9258(18)42827-x;
RA   Lebeau M.-C., Massol N., Herrick J., Faber L.E., Renoir J.-M., Radanyi C.,
RA   Baulieu E.-E.;
RT   "P59, an hsp 90-binding protein. Cloning and sequencing of its cDNA and
RT   preparation of a peptide-directed polyclonal antibody.";
RL   J. Biol. Chem. 267:4281-4284(1992).
RN   [2]
RP   PROTEIN SEQUENCE OF 2-26.
RC   STRAIN=New Zealand white; TISSUE=Liver;
RX   PubMed=8579355; DOI=10.1006/abbi.1996.0039;
RA   Deshpande K.L., Seubert P.H., Tillman D.M., Farkas W.R., Katze J.R.;
RT   "Cloning and characterization of cDNA encoding the rabbit tRNA-guanine
RT   transglycosylase 60-kilodalton subunit.";
RL   Arch. Biochem. Biophys. 326:1-7(1996).
RN   [3]
RP   DOMAINS.
RX   PubMed=1631118; DOI=10.1073/pnas.89.14.6270;
RA   Callebaut I., Renoir J.-M., Lebeau M.-C., Massol N., Burny A.,
RA   Baulieu E.-E., Mornon J.-P.;
RT   "An immunophilin that binds M(r) 90,000 heat shock protein: main structural
RT   features of a mammalian p59 protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 89:6270-6274(1992).
RN   [4]
RP   PPIASE ACTIVITY.
RX   PubMed=8216288; DOI=10.1006/bbrc.1993.2229;
RA   Chambraud B., Rouviere-Fourmy N., Radanyi C., Hsiao K., Peattie D.A.,
RA   Livingston D.J., Baulieu E.E.;
RT   "Overexpression of p59-HBI (FKBP59), full length and domains, and
RT   characterization of PPlase activity.";
RL   Biochem. Biophys. Res. Commun. 196:160-166(1993).
RN   [5]
RP   INTERACTION WITH GLMN.
RX   PubMed=8955134; DOI=10.1074/jbc.271.51.32923;
RA   Chambraud B., Radanyi C., Camonis J.H., Shazand K., Rajkowski K.,
RA   Baulieu E.-E.;
RT   "FAP48, a new protein that forms specific complexes with both immunophilins
RT   FKBP59 and FKBP12. Prevention by the immunosuppressant drugs FK506 and
RT   rapamycin.";
RL   J. Biol. Chem. 271:32923-32929(1996).
RN   [6]
RP   IDENTIFICATION IN A COMPLEX WITH NR3C1 AND HSP90AA1.
RX   PubMed=9195923; DOI=10.1074/jbc.272.26.16224;
RA   Silverstein A.M., Galigniana M.D., Chen M.S., Owens-Grillo J.K.,
RA   Chinkers M., Pratt W.B.;
RT   "Protein phosphatase 5 is a major component of glucocorticoid
RT   receptor.hsp90 complexes with properties of an FK506-binding
RT   immunophilin.";
RL   J. Biol. Chem. 272:16224-16230(1997).
RN   [7]
RP   PHOSPHORYLATION AT THR-143 BY CK2.
RX   PubMed=9405642; DOI=10.1073/pnas.94.26.14500;
RA   Miyata Y., Chambraud B., Radanyi C., Leclerc J., Lebeau M.-C.,
RA   Renoir J.-M., Shirai R., Catelli M.-G., Yahara I., Baulieu E.-E.;
RT   "Phosphorylation of the immunosuppressant FK506-binding protein FKBP52 by
RT   casein kinase II: regulation of HSP90-binding activity of FKBP52.";
RL   Proc. Natl. Acad. Sci. U.S.A. 94:14500-14505(1997).
RN   [8]
RP   INTERACTION WITH NR3C1; DYNEIN AND HSP90.
RX   PubMed=10601253; DOI=10.1074/jbc.274.52.36980;
RA   Silverstein A.M., Galigniana M.D., Kanelakis K.C., Radanyi C.,
RA   Renoir J.-M., Pratt W.B.;
RT   "Different regions of the immunophilin FKBP52 determine its association
RT   with the glucocorticoid receptor, hsp90, and cytoplasmic dynein.";
RL   J. Biol. Chem. 274:36980-36986(1999).
RN   [9]
RP   INTERACTION WITH PHYH.
RX   PubMed=10051602; DOI=10.1073/pnas.96.5.2104;
RA   Chambraud B., Radanyi C., Camonis J.H., Rajkowski K., Schumacher M.,
RA   Baulieu E.-E.;
RT   "Immunophilins, Refsum disease, and lupus nephritis: the peroxisomal enzyme
RT   phytanoyl-CoA alpha-hydroxylase is a new FKBP-associated protein.";
RL   Proc. Natl. Acad. Sci. U.S.A. 96:2104-2109(1999).
RN   [10]
RP   FUNCTION AS A CO-CHAPERONE, AND DOMAINS.
RX   PubMed=11473108; DOI=10.1074/jbc.m102595200;
RA   Pirkl F., Fischer E., Modrow S., Buchner J.;
RT   "Localization of the chaperone domain of FKBP52.";
RL   J. Biol. Chem. 276:37034-37041(2001).
RN   [11]
RP   STRUCTURE BY NMR OF 1-149.
RX   PubMed=8780506; DOI=10.1021/bi960975p;
RA   Craescu C.T., Rouviere N., Popescu A., Cerpolini E., Lebeau M.-C.,
RA   Baulieu E.-E., Mispelter J.;
RT   "Three-dimensional structure of the immunophilin-like domain of FKBP59 in
RT   solution.";
RL   Biochemistry 35:11045-11052(1996).
CC   -!- FUNCTION: Immunophilin protein with PPIase and co-chaperone activities.
CC       Component of steroid receptors heterocomplexes through interaction with
CC       heat-shock protein 90 (HSP90). May play a role in the intracellular
CC       trafficking of heterooligomeric forms of steroid hormone receptors
CC       between cytoplasm and nuclear compartments. The isomerase activity
CC       controls neuronal growth cones via regulation of TRPC1 channel opening.
CC       Acts also as a regulator of microtubule dynamics by inhibiting MAPT/TAU
CC       ability to promote microtubule assembly. May have a protective role
CC       against oxidative stress in mitochondria (By similarity). {ECO:0000250,
CC       ECO:0000269|PubMed:11473108}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=[protein]-peptidylproline (omega=180) = [protein]-
CC         peptidylproline (omega=0); Xref=Rhea:RHEA:16237, Rhea:RHEA-
CC         COMP:10747, Rhea:RHEA-COMP:10748, ChEBI:CHEBI:83833,
CC         ChEBI:CHEBI:83834; EC=5.2.1.8;
CC   -!- ACTIVITY REGULATION: Inhibited by FK506. {ECO:0000250}.
CC   -!- SUBUNIT: Homodimer (By similarity). Interacts with GLMN; rapamycin and
CC       FK506 abolish the interaction with GLMN in a dose dependent manner
CC       (PubMed:8955134). Associates with HSP90AA1 and HSP70 in steroid hormone
CC       receptor complexes. Also interacts with peroxisomal phytanoyl-CoA
CC       alpha-hydroxylase (PHYH) (PubMed:10051602). Interacts with NR3C1 and
CC       dynein. Interacts with HSF1 in the HSP90 complex. Associates with
CC       tubulin. Interacts with MAPT/TAU (By similarity). Interacts (via TPR
CC       domain) with S100A1, S100A2 and S100A6; the interaction is Ca(2+)
CC       dependent. Interaction with S100A1 and S100A2 (but not with S100A6)
CC       leads to inhibition of FKBP4-HSP90 interaction. Interacts with dynein;
CC       causes partially NR3C1 transport to the nucleus. {ECO:0000250,
CC       ECO:0000250|UniProtKB:Q9QVC8, ECO:0000269|PubMed:10051602,
CC       ECO:0000269|PubMed:10601253, ECO:0000269|PubMed:8955134,
CC       ECO:0000269|PubMed:9195923}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm, cytosol {ECO:0000250}. Mitochondrion
CC       {ECO:0000250}. Nucleus. Cytoplasm, cytoskeleton {ECO:0000250}.
CC       Note=Shuttles from mitochondria to nucleus; co-localizes in
CC       mitochondria with the glucocorticoid receptor. {ECO:0000250}.
CC   -!- DOMAIN: The C-terminal region (AA 375-458) is required to prevent
CC       tubulin polymerization. {ECO:0000250}.
CC   -!- DOMAIN: The PPIase activity is mainly due to the first PPIase FKBP-type
CC       domain (1-138 AA).
CC   -!- DOMAIN: The chaperone activity resides in the C-terminal region, mainly
CC       between amino acids 264 and 400.
CC   -!- DOMAIN: The TPR repeats mediate mitochondrial localization.
CC       {ECO:0000250}.
CC   -!- PTM: Phosphorylation by CK2 results in loss of HSP90 binding activity.
CC       {ECO:0000269|PubMed:9405642}.
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DR   EMBL; M84474; AAA31438.1; -; mRNA.
DR   EMBL; M84988; AAA31439.1; -; mRNA.
DR   PIR; A42386; A42386.
DR   RefSeq; NP_001075779.1; NM_001082310.1.
DR   PDB; 1ROT; NMR; -; A=4-148.
DR   PDB; 1ROU; NMR; -; A=4-148.
DR   PDBsum; 1ROT; -.
DR   PDBsum; 1ROU; -.
DR   AlphaFoldDB; P27124; -.
DR   SMR; P27124; -.
DR   BioGRID; 1172171; 1.
DR   STRING; 9986.ENSOCUP00000048194; -.
DR   iPTMnet; P27124; -.
DR   PaxDb; 9986-ENSOCUP00000012554; -.
DR   Ensembl; ENSOCUT00000014603.4; ENSOCUP00000012554.3; ENSOCUG00000014603.4.
DR   GeneID; 100009148; -.
DR   KEGG; ocu:100009148; -.
DR   CTD; 2288; -.
DR   eggNOG; KOG0543; Eukaryota.
DR   GeneTree; ENSGT00940000157200; -.
DR   HOGENOM; CLU_013615_13_1_1; -.
DR   InParanoid; P27124; -.
DR   OMA; FGAEGNE; -.
DR   OrthoDB; 25281at2759; -.
DR   EvolutionaryTrace; P27124; -.
DR   Proteomes; UP000001811; Chromosome 8.
DR   Bgee; ENSOCUG00000014603; Expressed in testis and 17 other cell types or tissues.
DR   GO; GO:0044295; C:axonal growth cone; ISS:UniProtKB.
DR   GO; GO:0005829; C:cytosol; ISS:UniProtKB.
DR   GO; GO:0005874; C:microtubule; IEA:UniProtKB-KW.
DR   GO; GO:0005739; C:mitochondrion; IEA:UniProtKB-SubCell.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0003755; F:peptidyl-prolyl cis-trans isomerase activity; ISS:UniProtKB.
DR   GO; GO:0048156; F:tau protein binding; IPI:UniProtKB.
DR   GO; GO:0061077; P:chaperone-mediated protein folding; ISS:UniProtKB.
DR   GO; GO:0031111; P:negative regulation of microtubule polymerization or depolymerization; IDA:UniProtKB.
DR   GO; GO:0010977; P:negative regulation of neuron projection development; IDA:UniProtKB.
DR   Gene3D; 3.10.50.40; -; 2.
DR   Gene3D; 1.25.40.10; Tetratricopeptide repeat domain; 1.
DR   InterPro; IPR046357; PPIase_dom_sf.
DR   InterPro; IPR001179; PPIase_FKBP_dom.
DR   InterPro; IPR011990; TPR-like_helical_dom_sf.
DR   InterPro; IPR001440; TPR_1.
DR   InterPro; IPR013105; TPR_2.
DR   InterPro; IPR019734; TPR_repeat.
DR   PANTHER; PTHR46512; PEPTIDYLPROLYL ISOMERASE; 1.
DR   PANTHER; PTHR46512:SF9; TETRATRICOPEPTIDE REPEAT DOMAIN 9; 1.
DR   Pfam; PF00254; FKBP_C; 2.
DR   Pfam; PF00515; TPR_1; 1.
DR   Pfam; PF07719; TPR_2; 1.
DR   SMART; SM00028; TPR; 3.
DR   SUPFAM; SSF54534; FKBP-like; 2.
DR   SUPFAM; SSF48452; TPR-like; 1.
DR   PROSITE; PS50059; FKBP_PPIASE; 2.
DR   PROSITE; PS50005; TPR; 3.
DR   PROSITE; PS50293; TPR_REGION; 2.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Chaperone; Cytoplasm; Cytoskeleton;
KW   Direct protein sequencing; Isomerase; Isopeptide bond; Methylation;
KW   Microtubule; Mitochondrion; Nucleus; Phosphoprotein; Reference proteome;
KW   Repeat; Rotamase; TPR repeat; Ubl conjugation.
FT   CHAIN           1..458
FT                   /note="Peptidyl-prolyl cis-trans isomerase FKBP4"
FT                   /id="PRO_0000391470"
FT   INIT_MET        1
FT                   /note="Removed; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   CHAIN           2..458
FT                   /note="Peptidyl-prolyl cis-trans isomerase FKBP4, N-
FT                   terminally processed"
FT                   /id="PRO_0000075320"
FT   DOMAIN          50..138
FT                   /note="PPIase FKBP-type 1"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00277"
FT   DOMAIN          167..253
FT                   /note="PPIase FKBP-type 2"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00277"
FT   REPEAT          270..303
FT                   /note="TPR 1"
FT   REPEAT          319..352
FT                   /note="TPR 2"
FT   REPEAT          353..386
FT                   /note="TPR 3"
FT   REGION          1..24
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          267..400
FT                   /note="Interaction with tubulin"
FT                   /evidence="ECO:0000250"
FT   REGION          423..458
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        423..448
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOD_RES         1
FT                   /note="N-acetylmethionine; in peptidyl-prolyl cis-trans
FT                   isomerase FKBP4; alternate"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   MOD_RES         2
FT                   /note="N-acetylthreonine; in peptidyl-prolyl cis-trans
FT                   isomerase FKBP4, N-terminally processed; partial"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   MOD_RES         143
FT                   /note="Phosphothreonine; by CK2"
FT                   /evidence="ECO:0000269|PubMed:9405642"
FT   MOD_RES         220
FT                   /note="Phosphotyrosine"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   MOD_RES         282
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   MOD_RES         373
FT                   /note="Omega-N-methylarginine"
FT                   /evidence="ECO:0000250|UniProtKB:P30416"
FT   MOD_RES         450
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   MOD_RES         452
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   CROSSLNK        441
FT                   /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT                   G-Cter in SUMO1)"
FT                   /evidence="ECO:0000250|UniProtKB:Q02790"
FT   CONFLICT        15
FT                   /note="S -> H (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        21..22
FT                   /note="EG -> FI (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        26
FT                   /note="S -> T (in Ref. 2; AA sequence)"
FT                   /evidence="ECO:0000305"
FT   STRAND          24..26
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   TURN            27..29
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          33..39
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          52..61
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   TURN            62..64
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          65..69
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   HELIX           70..73
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          77..80
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   TURN            81..83
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   HELIX           88..95
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          102..107
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   HELIX           109..111
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   TURN            112..116
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   TURN            119..121
FT                   /evidence="ECO:0007829|PDB:1ROT"
FT   STRAND          128..136
FT                   /evidence="ECO:0007829|PDB:1ROT"
SQ   SEQUENCE   458 AA;  51475 MW;  2EE25D561391DFF0 CRC64;
     MTAEEMKAAE SGAQSAPLPL EGVDISPKQD EGVLKVIKRE GTGTETPMIG DRVFVHYTGW
     LLDGTKFDSS LDRKDKFSFD LGKGEVIKAW DIAVATMKVG ELCRITCKPE YAYGSAGSPP
     KIPPNATLVF EVELFEFKGE DLTDDEDGGI IRRIRTRGEG YARPNDGAIV EVALEGYYKD
     RLFDQRELRF EVGEGESLDL PCGLEKAIQR MEKGEHSILY LKPSYAFGNA GKEKFQIPPY
     AELKYEVHLK SFEKAKESWE MSSEEKLEQS AIVKERGTVY FKEGKYKQAL LQYKKIVSWL
     EYESSFSSEE VQKAQALRLA SHLNLAMCHL KLQAFSAAVE SCNKALELDS NNEKGLFRRG
     EAHLAVNDFD LARADFQKVL QLYPSNKAAK AQLAVCQQRI RKQIAREKKL YANMFERLAE
     EENKAKAEVA AGDHPMDTEM KDERNDVAGS QSQVETEA
//