ID   MKLN1_RAT               Reviewed;         735 AA.
AC   Q99PV3;
DT   10-OCT-2002, integrated into UniProtKB/Swiss-Prot.
DT   01-JUN-2001, sequence version 1.
DT   27-MAR-2024, entry version 130.
DE   RecName: Full=Muskelin;
GN   Name=Mkln1; Synonyms=Msk;
OS   Rattus norvegicus (Rat).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae;
OC   Murinae; Rattus.
OX   NCBI_TaxID=10116;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], INTERACTION WITH PTGER3, AND SUBCELLULAR
RP   LOCATION.
RX   PubMed=11006128; DOI=10.1006/bbrc.2000.3467;
RA   Hasegawa H., Katoh H., Fujita H., Mori K., Negishi M.;
RT   "Receptor isoform-specific interaction of prostaglandin EP3 receptor with
RT   muskelin.";
RL   Biochem. Biophys. Res. Commun. 276:350-354(2000).
RN   [2]
RP   INTERACTION WITH GABRA1.
RX   PubMed=21482357; DOI=10.1016/j.neuron.2011.03.008;
RA   Heisler F.F., Loebrich S., Pechmann Y., Maier N., Zivkovic A.R., Tokito M.,
RA   Hausrat T.J., Schweizer M., Baehring R., Holzbaur E.L., Schmitz D.,
RA   Kneussel M.;
RT   "Muskelin regulates actin filament- and microtubule-based GABA(A) receptor
RT   transport in neurons.";
RL   Neuron 70:66-81(2011).
RN   [3] {ECO:0007744|PDB:4OYU}
RP   X-RAY CRYSTALLOGRAPHY (1.80 ANGSTROMS) OF 12-205, FUNCTION, SUBUNIT,
RP   DOMAIN, SUBCELLULAR LOCATION, AND MUTAGENESIS OF TYR-53; PHE-143; ASN-144;
RP   CYS-180; PHE-184; ARG-185 AND LEU-196.
RX   PubMed=25579817; DOI=10.1016/j.str.2014.11.016;
RA   Delto C.F., Heisler F.F., Kuper J., Sander B., Kneussel M., Schindelin H.;
RT   "The LisH motif of muskelin is crucial for oligomerization and governs
RT   intracellular localization.";
RL   Structure 23:364-373(2015).
CC   -!- FUNCTION: Component of the CTLH E3 ubiquitin-protein ligase complex
CC       that selectively accepts ubiquitin from UBE2H and mediates
CC       ubiquitination and subsequent proteasomal degradation of the
CC       transcription factor HBP1 (By similarity). Required for internalization
CC       of the GABA receptor GABRA1 from the cell membrane via endosomes and
CC       subsequent GABRA1 degradation (PubMed:25579817). Acts as a mediator of
CC       cell spreading and cytoskeletal responses to the extracellular matrix
CC       component THBS1 (By similarity). {ECO:0000250|UniProtKB:O89050,
CC       ECO:0000250|UniProtKB:Q9UL63, ECO:0000269|PubMed:25579817}.
CC   -!- SUBUNIT: Homodimer; may form higher oligomers (PubMed:25579817).
CC       Identified in the CTLH complex that contains GID4, RANBP9 and/or
CC       RANBP10, MKLN1, MAEA, RMND5A (or alternatively its paralog RMND5B),
CC       GID8, ARMC8, WDR26 and YPEL5. Within this complex, MAEA, RMND5A (or
CC       alternatively its paralog RMND5B), GID8, WDR26, and RANBP9 and/or
CC       RANBP10 form the catalytic core, while GID4, MKLN1, ARMC8 and YPEL5
CC       have ancillary roles (By similarity). Interacts with RANBP9 (By
CC       similarity). Part of a complex consisting of RANBP9, MKLN1 and GID8 (By
CC       similarity). Interacts with GABRA1 (PubMed:21482357). Interacts with
CC       the C-terminal tail of PTGER3 (PubMed:11006128).
CC       {ECO:0000250|UniProtKB:O89050, ECO:0000250|UniProtKB:Q9UL63,
CC       ECO:0000269|PubMed:11006128, ECO:0000269|PubMed:21482357,
CC       ECO:0000269|PubMed:25579817}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000269|PubMed:11006128,
CC       ECO:0000269|PubMed:25579817}. Cell projection, ruffle
CC       {ECO:0000250|UniProtKB:O89050}. Cytoplasm, cell cortex
CC       {ECO:0000250|UniProtKB:O89050}. Synapse {ECO:0000250|UniProtKB:O89050}.
CC       Postsynapse {ECO:0000250|UniProtKB:O89050}. Note=Colocalizes with
CC       GABRA1 at synapses and in postsynaptic regions. Colocalizes with actin
CC       fibers in the cell cortex. {ECO:0000250|UniProtKB:O89050}.
CC   -!- DOMAIN: The LisH mediates head to tail dimerization.
CC       {ECO:0000269|PubMed:25579817}.
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DR   EMBL; AB046442; BAB21439.1; -; mRNA.
DR   RefSeq; NP_112649.1; NM_031359.1.
DR   PDB; 4OYU; X-ray; 1.80 A; A/B=12-205.
DR   PDBsum; 4OYU; -.
DR   AlphaFoldDB; Q99PV3; -.
DR   SMR; Q99PV3; -.
DR   STRING; 10116.ENSRNOP00000075084; -.
DR   PhosphoSitePlus; Q99PV3; -.
DR   PaxDb; 10116-ENSRNOP00000016633; -.
DR   Ensembl; ENSRNOT00000081707.2; ENSRNOP00000075084.2; ENSRNOG00000054514.2.
DR   GeneID; 83536; -.
DR   KEGG; rno:83536; -.
DR   UCSC; RGD:620076; rat.
DR   AGR; RGD:620076; -.
DR   CTD; 4289; -.
DR   RGD; 620076; Mkln1.
DR   eggNOG; KOG2437; Eukaryota.
DR   GeneTree; ENSGT00390000001702; -.
DR   InParanoid; Q99PV3; -.
DR   OMA; NKQDYKH; -.
DR   OrthoDB; 2714048at2759; -.
DR   PhylomeDB; Q99PV3; -.
DR   TreeFam; TF323659; -.
DR   PRO; PR:Q99PV3; -.
DR   Proteomes; UP000002494; Chromosome 4.
DR   GO; GO:0005938; C:cell cortex; ISS:UniProtKB.
DR   GO; GO:0005737; C:cytoplasm; ISO:RGD.
DR   GO; GO:0005829; C:cytosol; IDA:UniProtKB.
DR   GO; GO:0005654; C:nucleoplasm; ISO:RGD.
DR   GO; GO:0098794; C:postsynapse; IEA:UniProtKB-SubCell.
DR   GO; GO:0001726; C:ruffle; ISS:UniProtKB.
DR   GO; GO:0000151; C:ubiquitin ligase complex; ISO:RGD.
DR   GO; GO:0042802; F:identical protein binding; ISO:RGD.
DR   GO; GO:0042803; F:protein homodimerization activity; IDA:UniProtKB.
DR   GO; GO:0030036; P:actin cytoskeleton organization; ISS:UniProtKB.
DR   GO; GO:0007160; P:cell-matrix adhesion; ISS:UniProtKB.
DR   GO; GO:0008360; P:regulation of cell shape; ISS:UniProtKB.
DR   GO; GO:0002090; P:regulation of receptor internalization; IMP:UniProtKB.
DR   Gene3D; 2.60.120.260; Galactose-binding domain-like; 1.
DR   Gene3D; 2.120.10.80; Kelch-type beta propeller; 2.
DR   InterPro; IPR006595; CTLH_C.
DR   InterPro; IPR011043; Gal_Oxase/kelch_b-propeller.
DR   InterPro; IPR008979; Galactose-bd-like_sf.
DR   InterPro; IPR015915; Kelch-typ_b-propeller.
DR   InterPro; IPR006652; Kelch_1.
DR   InterPro; IPR006594; LisH.
DR   InterPro; IPR010565; Muskelin_N.
DR   PANTHER; PTHR15526; MUSKELIN; 1.
DR   PANTHER; PTHR15526:SF5; MUSKELIN; 1.
DR   Pfam; PF01344; Kelch_1; 1.
DR   Pfam; PF13415; Kelch_3; 1.
DR   Pfam; PF06588; Muskelin_N; 1.
DR   SMART; SM00667; LisH; 1.
DR   SUPFAM; SSF50965; Galactose oxidase, central domain; 1.
DR   SUPFAM; SSF49785; Galactose-binding domain-like; 1.
DR   SUPFAM; SSF117281; Kelch motif; 1.
DR   PROSITE; PS50897; CTLH; 1.
DR   PROSITE; PS50896; LISH; 1.
PE   1: Evidence at protein level;
KW   3D-structure; Acetylation; Cell projection; Cytoplasm; Kelch repeat;
KW   Reference proteome; Repeat; Synapse.
FT   INIT_MET        1
FT                   /note="Removed"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UL63"
FT   CHAIN           2..735
FT                   /note="Muskelin"
FT                   /id="PRO_0000119140"
FT   DOMAIN          172..204
FT                   /note="LisH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00126"
FT   DOMAIN          206..258
FT                   /note="CTLH"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00058"
FT   REPEAT          284..330
FT                   /note="Kelch 1"
FT   REPEAT          339..391
FT                   /note="Kelch 2"
FT   REPEAT          400..458
FT                   /note="Kelch 3"
FT   REPEAT          469..515
FT                   /note="Kelch 4"
FT   REPEAT          526..578
FT                   /note="Kelch 5"
FT   REPEAT          597..651
FT                   /note="Kelch 6"
FT   MOD_RES         2
FT                   /note="N-acetylalanine"
FT                   /evidence="ECO:0000250|UniProtKB:Q9UL63"
FT   MUTAGEN         53
FT                   /note="Y->A: Reduced head to tail dimerization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         143
FT                   /note="F->A: Strongly reduced head to tail dimerization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         144
FT                   /note="N->R: Loss of head to tail dimerization. Causes loss
FT                   of location in the cytosol and accumulation in the nucleus.
FT                   No effect on GABA receptor internalization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         180
FT                   /note="C->S: Reduced head to tail dimerization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         184
FT                   /note="F->A: Reduced head to tail dimerization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         184
FT                   /note="F->E: Strongly reduced head to tail dimerization and
FT                   strongly reduced GABA receptor internalization; when
FT                   associated with Q-196. Causes loss of location in the
FT                   cytosol and accumulation in the nucleus; when associated
FT                   with Q-196."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         185
FT                   /note="R->A: Reduced head to tail dimerization."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   MUTAGEN         196
FT                   /note="L->Q: Strongly reduced head to tail dimerization and
FT                   strongly reduced GABA receptor internalization; when
FT                   associated with E-184. Causes loss of location in the
FT                   cytosol and accumulation in the nucleus; when associated
FT                   with E-184."
FT                   /evidence="ECO:0000269|PubMed:25579817"
FT   STRAND          18..24
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   HELIX           32..36
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          46..48
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          52..54
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          58..74
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          83..97
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          99..104
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          108..110
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          113..116
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          128..140
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   STRAND          149..155
FT                   /evidence="ECO:0007829|PDB:4OYU"
FT   HELIX           158..186
FT                   /evidence="ECO:0007829|PDB:4OYU"
SQ   SEQUENCE   735 AA;  84834 MW;  79BD0BBF74419E76 CRC64;
     MAAGGAVAAA PECRLLPYAL HKWSSFSSTY LPENILVDKP NDQSSRWSSE SNYPPQYLIL
     KLERPAIVQN ITFGKYEKTH VCNLKKFKVF GGMNEENMTE LLSSGLKNDY NKETFTLKHK
     IDEQMFPCRF IKIVPLLSWG PSFNFSIWYV ELSGIDDPDI VQPCLNWYSK YREQEAIRLC
     LKHFRQHNYT EAFESLQKKT KIALEHPMLT DMHDKLVLKG DFDACEELIE KAVNDGLFNQ
     YISQQEYKPR WSQIIPKSTK GDGEDNRPGM RGGHQMVIDV QTETVYLFGG WDGTQDLADF
     WAYSVKENQW TCISRDTEKE NGPSARSCHK MCIDIQRRQI YTLGRYLDSS VRNSKSLKSD
     FYRYDIDTNT WMLLSEDTAA DGGPKLVFDH QMCMDSEKHM IYTFGGRILT CNGSVDDSRA
     SEPQFSGLFA FNCQCQTWKL LREDSCNAGP EDIQSRIGHC MLFHSKNRCL YVFGGQRSKT
     YLNDFFSYDV DSDHVDIISD GTKKDSGMVP MTGFTQRATI DPELNEIHVL SGLSKDKEKR
     EENVRNSFWI YDIVRNSWSC VYKNDQAAKE NLSKSLQEEE PCPRFAHQLV YDELHKVHYL
     FGGNPGKSCS PKMRLDDFWS LKLCRPSKDY LLRHCKYLIR KHRFEEKAQM DPLSALKYLQ
     NDLYITVDHS DPEETKEFQL LASALFKSGS DFTALGFSDV DHTYAQRTQL FDTLVNFFPD
     SMTPPKGNLV DLITL
//