NHLC1_MOUSE
ID NHLC1_MOUSE Reviewed; 401 AA.
AC Q8BR37;
DT 19-JUL-2004, integrated into UniProtKB/Swiss-Prot.
DT 01-MAR-2003, sequence version 1.
DT 03-AUG-2022, entry version 142.
DE RecName: Full=E3 ubiquitin-protein ligase NHLRC1;
DE EC=2.3.2.27;
DE AltName: Full=Malin;
DE AltName: Full=NHL repeat-containing protein 1;
DE AltName: Full=RING-type E3 ubiquitin transferase NHLRC1 {ECO:0000305};
GN Name=Nhlrc1; Synonyms=Epm2b;
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=12958597; DOI=10.1038/ng1238;
RA Chan E.M., Young E.J., Ianzano L., Munteanu I., Zhao X.,
RA Christopoulos C.C., Avanzini G., Elia M., Ackerley C.A., Jovic N.J.,
RA Bohlega S., Andermann E., Rouleau G.A., Delgado-Escueta A.V.,
RA Minassian B.A., Scherer S.W.;
RT "Mutations in NHLRC1 cause progressive myoclonus epilepsy.";
RL Nat. Genet. 35:125-127(2003).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
RC STRAIN=C57BL/6J; TISSUE=Brain;
RX PubMed=16141072; DOI=10.1126/science.1112014;
RA Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N.,
RA Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K.,
RA Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.,
RA Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R.,
RA Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T.,
RA Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A.,
RA Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B.,
RA Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M.,
RA Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S.,
RA Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E.,
RA Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D.,
RA Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M.,
RA Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H.,
RA Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V.,
RA Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S.,
RA Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H.,
RA Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N.,
RA Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F.,
RA Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G.,
RA Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z.,
RA Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C.,
RA Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y.,
RA Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S.,
RA Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K.,
RA Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R.,
RA van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H.,
RA Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M.,
RA Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C.,
RA Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S.,
RA Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K.,
RA Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M.,
RA Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C.,
RA Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A.,
RA Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.;
RT "The transcriptional landscape of the mammalian genome.";
RL Science 309:1559-1563(2005).
RN [3]
RP FUNCTION, AND COMPLEX FORMATION WITH EPM2A AND HSP70.
RX PubMed=19036738; DOI=10.1093/hmg/ddn398;
RA Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S.,
RA Parihar R., Ganesh S.;
RT "The malin-laforin complex suppresses the cellular toxicity of misfolded
RT proteins by promoting their degradation through the ubiquitin-proteasome
RT system.";
RL Hum. Mol. Genet. 18:688-700(2009).
RN [4]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=21077101; DOI=10.1002/ana.22156;
RA Turnbull J., Wang P., Girard J.M., Ruggieri A., Wang T.J., Draginov A.G.,
RA Kameka A.P., Pencea N., Zhao X., Ackerley C.A., Minassian B.A.;
RT "Glycogen hyperphosphorylation underlies lafora body formation.";
RL Ann. Neurol. 68:925-933(2010).
RN [5]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22186026; DOI=10.1093/hmg/ddr590;
RA Criado O., Aguado C., Gayarre J., Duran-Trio L., Garcia-Cabrero A.M.,
RA Vernia S., San Millan B., Heredia M., Roma-Mateo C., Mouron S.,
RA Juana-Lopez L., Dominguez M., Navarro C., Serratosa J.M., Sanchez M.,
RA Sanz P., Bovolenta P., Knecht E., Rodriguez de Cordoba S.;
RT "Lafora bodies and neurological defects in malin-deficient mice correlate
RT with impaired autophagy.";
RL Hum. Mol. Genet. 21:1521-1533(2012).
RN [6]
RP FUNCTION, AND DISRUPTION PHENOTYPE.
RX PubMed=22669944; DOI=10.1074/jbc.m111.331611;
RA Tiberia E., Turnbull J., Wang T., Ruggieri A., Zhao X.C., Pencea N.,
RA Israelian J., Wang Y., Ackerley C.A., Wang P., Liu Y., Minassian B.A.;
RT "Increased laforin and laforin binding to glycogen underlie Lafora body
RT formation in malin-deficient Lafora disease.";
RL J. Biol. Chem. 287:25650-25659(2012).
CC -!- FUNCTION: E3 ubiquitin-protein ligase. Together with the phosphatase
CC EPM2A/laforin, appears to be involved in the clearance of toxic
CC polyglucosan and protein aggregates via multiple pathways. In complex
CC with EPM2A/laforin and HSP70, suppresses the cellular toxicity of
CC misfolded proteins by promoting their degradation through the
CC ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting
CC protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-
CC dependent manner and targets them for proteasome-dependent degradation,
CC thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin
CC and ubiquitinates AGL and targets them for proteasome-dependent
CC degradation. Also promotes proteasome-independent protein degradation
CC through the macroautophagy pathway. {ECO:0000269|PubMed:19036738,
CC ECO:0000269|PubMed:21077101, ECO:0000269|PubMed:22186026,
CC ECO:0000269|PubMed:22669944}.
CC -!- CATALYTIC ACTIVITY:
CC Reaction=S-ubiquitinyl-[E2 ubiquitin-conjugating enzyme]-L-cysteine +
CC [acceptor protein]-L-lysine = [E2 ubiquitin-conjugating enzyme]-L-
CC cysteine + N(6)-ubiquitinyl-[acceptor protein]-L-lysine.;
CC EC=2.3.2.27;
CC -!- PATHWAY: Protein modification; protein ubiquitination.
CC -!- SUBUNIT: Interacts with AGL. Interacts (via the NHL repeats) with
CC EPM2A/laforin (By similarity). Forms a complex with EPM2A/laforin and
CC HSP70. Interacts with PRDM8 (By similarity).
CC {ECO:0000250|UniProtKB:Q6VVB1}.
CC -!- SUBCELLULAR LOCATION: Endoplasmic reticulum {ECO:0000250}. Nucleus
CC {ECO:0000250}. Note=Localizes at the endoplasmic reticulum and, to a
CC lesser extent, in the nucleus. {ECO:0000250}.
CC -!- DOMAIN: The RING domain is essential for ubiquitin E3 ligase activity.
CC {ECO:0000250}.
CC -!- DISRUPTION PHENOTYPE: Significant impairment of motor activity,
CC coordination and balance; spontaneous myoclonic seizures; and decreases
CC in episodic memory. 3- and 6-month old mice contain numerous large
CC insoluble aggregates composed mainly of polyglucosans called Lafora
CC bodies (LBs) in skeletal muscle, liver, heart and brain. Glycogen
CC levels are increased 1.6-fold and 1.2-fold respectively in skeletal
CC muscle and liver of 6-month old mice. Glycogen phosphate levels are
CC increased 1.5-fold in skeletal muscle and liver of 6-month old mice. In
CC brain extracts from 1-, 3- and 12-month old mice, total amounts of
CC Epm2b/laforin protein (but not mRNA) are increased. In brain and
CC embryonic fibroblast cells, levels of the autophagy marker
CC Map1lc3b/LC3-II are reduced. In the brain, levels of the autophagy
CC dysfunction marker Sqstm1/p62 are increased.
CC {ECO:0000269|PubMed:21077101, ECO:0000269|PubMed:22186026,
CC ECO:0000269|PubMed:22669944}.
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DR EMBL; BK001499; DAA01953.1; -; mRNA.
DR EMBL; AK045746; BAC32478.1; -; mRNA.
DR CCDS; CCDS26487.1; -.
DR RefSeq; NP_780549.1; NM_175340.4.
DR AlphaFoldDB; Q8BR37; -.
DR SMR; Q8BR37; -.
DR BioGRID; 222784; 2.
DR STRING; 10090.ENSMUSP00000054990; -.
DR PhosphoSitePlus; Q8BR37; -.
DR MaxQB; Q8BR37; -.
DR PaxDb; Q8BR37; -.
DR PRIDE; Q8BR37; -.
DR ProteomicsDB; 287421; -.
DR Antibodypedia; 25182; 280 antibodies from 26 providers.
DR DNASU; 105193; -.
DR Ensembl; ENSMUST00000052747; ENSMUSP00000054990; ENSMUSG00000044231.
DR GeneID; 105193; -.
DR KEGG; mmu:105193; -.
DR UCSC; uc007qhp.2; mouse.
DR CTD; 378884; -.
DR MGI; MGI:2145264; Nhlrc1.
DR VEuPathDB; HostDB:ENSMUSG00000044231; -.
DR eggNOG; KOG2177; Eukaryota.
DR GeneTree; ENSGT00730000111361; -.
DR HOGENOM; CLU_696320_0_0_1; -.
DR InParanoid; Q8BR37; -.
DR OMA; RKLECPF; -.
DR OrthoDB; 711255at2759; -.
DR PhylomeDB; Q8BR37; -.
DR TreeFam; TF331018; -.
DR UniPathway; UPA00143; -.
DR BioGRID-ORCS; 105193; 1 hit in 72 CRISPR screens.
DR ChiTaRS; Nhlrc1; mouse.
DR PRO; PR:Q8BR37; -.
DR Proteomes; UP000000589; Chromosome 13.
DR RNAct; Q8BR37; protein.
DR Bgee; ENSMUSG00000044231; Expressed in interventricular septum and 179 other tissues.
DR ExpressionAtlas; Q8BR37; baseline and differential.
DR Genevisible; Q8BR37; MM.
DR GO; GO:0005783; C:endoplasmic reticulum; IEA:UniProtKB-SubCell.
DR GO; GO:0005634; C:nucleus; IDA:MGI.
DR GO; GO:0048471; C:perinuclear region of cytoplasm; IDA:MGI.
DR GO; GO:0046872; F:metal ion binding; IEA:UniProtKB-KW.
DR GO; GO:0061630; F:ubiquitin protein ligase activity; IDA:MGI.
DR GO; GO:0004842; F:ubiquitin-protein transferase activity; ISS:UniProtKB.
DR GO; GO:0006914; P:autophagy; IMP:MGI.
DR GO; GO:0044260; P:cellular macromolecule metabolic process; IMP:MGI.
DR GO; GO:0005978; P:glycogen biosynthetic process; IMP:MGI.
DR GO; GO:0005977; P:glycogen metabolic process; IMP:MGI.
DR GO; GO:0031398; P:positive regulation of protein ubiquitination; IDA:MGI.
DR GO; GO:0043161; P:proteasome-mediated ubiquitin-dependent protein catabolic process; IMP:MGI.
DR GO; GO:0000209; P:protein polyubiquitination; ISS:UniProtKB.
DR GO; GO:0016567; P:protein ubiquitination; IDA:MGI.
DR GO; GO:0010468; P:regulation of gene expression; IMP:MGI.
DR GO; GO:0045859; P:regulation of protein kinase activity; IMP:MGI.
DR GO; GO:1903076; P:regulation of protein localization to plasma membrane; IGI:MGI.
DR GO; GO:0001932; P:regulation of protein phosphorylation; IMP:MGI.
DR GO; GO:0031396; P:regulation of protein ubiquitination; IGI:MGI.
DR GO; GO:0034976; P:response to endoplasmic reticulum stress; IMP:MGI.
DR GO; GO:0006511; P:ubiquitin-dependent protein catabolic process; ISO:MGI.
DR Gene3D; 2.120.10.30; -; 1.
DR Gene3D; 3.30.40.10; -; 1.
DR InterPro; IPR011042; 6-blade_b-propeller_TolB-like.
DR InterPro; IPR001258; NHL_repeat.
DR InterPro; IPR001841; Znf_RING.
DR InterPro; IPR013083; Znf_RING/FYVE/PHD.
DR InterPro; IPR017907; Znf_RING_CS.
DR Pfam; PF14634; zf-RING_5; 1.
DR SMART; SM00184; RING; 1.
DR PROSITE; PS51125; NHL; 6.
DR PROSITE; PS00518; ZF_RING_1; 1.
DR PROSITE; PS50089; ZF_RING_2; 1.
PE 2: Evidence at transcript level;
KW Autophagy; Endoplasmic reticulum; Metal-binding; Nucleus;
KW Reference proteome; Repeat; Transferase; Ubl conjugation pathway; Zinc;
KW Zinc-finger.
FT CHAIN 1..401
FT /note="E3 ubiquitin-protein ligase NHLRC1"
FT /id="PRO_0000055981"
FT REPEAT 115..159
FT /note="NHL 1"
FT REPEAT 163..206
FT /note="NHL 2"
FT REPEAT 207..247
FT /note="NHL 3"
FT REPEAT 250..303
FT /note="NHL 4"
FT REPEAT 304..352
FT /note="NHL 5"
FT REPEAT 353..396
FT /note="NHL 6"
FT ZN_FING 28..74
FT /note="RING-type"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00175"
SQ SEQUENCE 401 AA; 42690 MW; 0A2AF7633B472372 CRC64;
MGEEATAVAA AGVRPELVRE AEVSLLECKV CFERFGHWQQ RRPRNLPCGH VVCLACVAAL
AHPRTLGLEC PFCRRACRAC DTSDCLPVLH LLELLGSTLH ASPAALSAAP FAPGTLTCYH
AFGGWGTLVN PTGLALCPKT GRVVVVHDGK RRVKIFDSGG GGAHQFGEKG DAAHDVKYPL
DVAVTNDCHV VVTDAGDCSL KVFDFFGQIK LVVGKQFSLP WGVEITPHNG VLVTDAEAGT
LHLLEADFPE GVLRRIERLQ AHLCSPRGLA VSWLTGAIAV LEHPCAFGRT GCNNTRVKVF
NSTMQLIGQV DSFGLNLLFP SKVTASAVTF DHQGNVIVAD TSGPAIVCLG KPEEFPALKP
IITHGLSRPV ALAFTKENSL LVLDTASHSI KVFKVMEGNG G
