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Protein

E3 ubiquitin-protein ligase NHLRC1

Gene

Nhlrc1

Organism
Mus musculus (Mouse)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at transcript leveli

Functioni

E3 ubiquitin-protein ligase. Together with the phosphatase EPM2A/laforin, appears to be involved in the clearance of toxic polyglucosan and protein aggregates via multiple pathways. In complex with EPM2A/laforin and HSP70, suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system (UPS). Ubiquitinates the glycogen-targeting protein phosphatase subunits PPP1R3C/PTG and PPP1R3D in a laforin-dependent manner and targets them for proteasome-dependent degradation, thus decreasing glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Also promotes proteasome-independent protein degradation through the macroautophagy pathway.4 Publications

Pathwayi: protein ubiquitination

This protein is involved in the pathway protein ubiquitination, which is part of Protein modification.
View all proteins of this organism that are known to be involved in the pathway protein ubiquitination and in Protein modification.

Regions

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri28 – 7447RING-typePROSITE-ProRule annotationAdd
BLAST

GO - Molecular functioni

GO - Biological processi

Complete GO annotation...

Keywords - Molecular functioni

Ligase

Keywords - Biological processi

Autophagy, Ubl conjugation pathway

Keywords - Ligandi

Metal-binding, Zinc

Enzyme and pathway databases

ReactomeiR-MMU-3322077. Glycogen synthesis.
UniPathwayiUPA00143.

Names & Taxonomyi

Protein namesi
Recommended name:
E3 ubiquitin-protein ligase NHLRC1 (EC:6.3.2.-)
Alternative name(s):
Malin
NHL repeat-containing protein 1
Gene namesi
Name:Nhlrc1
Synonyms:Epm2b
OrganismiMus musculus (Mouse)
Taxonomic identifieri10090 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresGliresRodentiaSciurognathiMuroideaMuridaeMurinaeMusMus
Proteomesi
  • UP000000589 Componenti: Chromosome 13

Organism-specific databases

MGIiMGI:2145264. Nhlrc1.

Subcellular locationi

  • Endoplasmic reticulum By similarity
  • Nucleus By similarity

  • Note: Localizes at the endoplasmic reticulum and, to a lesser extent, in the nucleus.By similarity

GO - Cellular componenti

  • endoplasmic reticulum Source: UniProtKB-SubCell
  • nucleus Source: UniProtKB
  • perinuclear region of cytoplasm Source: MGI
Complete GO annotation...

Keywords - Cellular componenti

Endoplasmic reticulum, Nucleus

Pathology & Biotechi

Disruption phenotypei

Significant impairment of motor activity, coordination and balance; spontaneous myoclonic seizures; and decreases in episodic memory. 3- and 6-month old mice contain numerous large insoluble aggregates composed mainly of polyglucosans called Lafora bodies (LBs) in skeletal muscle, liver, heart and brain. Glycogen levels are increased 1.6-fold and 1.2-fold respectively in skeletal muscle and liver of 6-month old mice. Glycogen phosphate levels are increased 1.5-fold in skeletal muscle and liver of 6-month old mice. In brain extracts from 1-, 3- and 12-month old mice, total amounts of Epm2b/laforin protein (but not mRNA) are increased. In brain and embryonic fibroblast cells, levels of the autophagy marker Map1lc3b/LC3-II are reduced. In the brain, levels of the autophagy dysfunction marker Sqstm1/p62 are increased.3 Publications

PTM / Processingi

Molecule processing

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Chaini1 – 401401E3 ubiquitin-protein ligase NHLRC1PRO_0000055981Add
BLAST

Proteomic databases

MaxQBiQ8BR37.
PaxDbiQ8BR37.
PRIDEiQ8BR37.

Expressioni

Gene expression databases

BgeeiQ8BR37.
CleanExiMM_NHLRC1.
ExpressionAtlasiQ8BR37. baseline and differential.
GenevisibleiQ8BR37. MM.

Interactioni

Subunit structurei

Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin (By similarity). Forms a complex with EPM2A/laforin and HSP70. Interacts with PRDM8 (By similarity).By similarity

Protein-protein interaction databases

BioGridi222784. 2 interactions.
STRINGi10090.ENSMUSP00000054990.

Structurei

3D structure databases

ProteinModelPortaliQ8BR37.
SMRiQ8BR37. Positions 25-98.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Repeati115 – 15945NHL 1Add
BLAST
Repeati163 – 20644NHL 2Add
BLAST
Repeati207 – 24741NHL 3Add
BLAST
Repeati250 – 30354NHL 4Add
BLAST
Repeati304 – 35249NHL 5Add
BLAST
Repeati353 – 39644NHL 6Add
BLAST

Domaini

The RING domain is essential for ubiquitin E3 ligase activity.By similarity

Sequence similaritiesi

Contains 6 NHL repeats.PROSITE-ProRule annotation
Contains 1 RING-type zinc finger.PROSITE-ProRule annotation

Zinc finger

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifierActions
Zinc fingeri28 – 7447RING-typePROSITE-ProRule annotationAdd
BLAST

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiENOG410ITF2. Eukaryota.
ENOG410ZMHC. LUCA.
GeneTreeiENSGT00730000111361.
HOGENOMiHOG000113780.
HOVERGENiHBG052617.
InParanoidiQ8BR37.
KOiK10602.
OMAiPRNLPCG.
OrthoDBiEOG7VX8W6.
PhylomeDBiQ8BR37.
TreeFamiTF331018.

Family and domain databases

Gene3Di2.120.10.30. 1 hit.
3.30.40.10. 1 hit.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR013017. NHL_repeat_subgr.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF14634. zf-RING_5. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS51125. NHL. 6 hits.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

Sequencei

Sequence statusi: Complete.

Q8BR37-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MGEEATAVAA AGVRPELVRE AEVSLLECKV CFERFGHWQQ RRPRNLPCGH
60 70 80 90 100
VVCLACVAAL AHPRTLGLEC PFCRRACRAC DTSDCLPVLH LLELLGSTLH
110 120 130 140 150
ASPAALSAAP FAPGTLTCYH AFGGWGTLVN PTGLALCPKT GRVVVVHDGK
160 170 180 190 200
RRVKIFDSGG GGAHQFGEKG DAAHDVKYPL DVAVTNDCHV VVTDAGDCSL
210 220 230 240 250
KVFDFFGQIK LVVGKQFSLP WGVEITPHNG VLVTDAEAGT LHLLEADFPE
260 270 280 290 300
GVLRRIERLQ AHLCSPRGLA VSWLTGAIAV LEHPCAFGRT GCNNTRVKVF
310 320 330 340 350
NSTMQLIGQV DSFGLNLLFP SKVTASAVTF DHQGNVIVAD TSGPAIVCLG
360 370 380 390 400
KPEEFPALKP IITHGLSRPV ALAFTKENSL LVLDTASHSI KVFKVMEGNG

G
Length:401
Mass (Da):42,690
Last modified:March 1, 2003 - v1
Checksum:i0A2AF7633B472372
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BK001499 mRNA. Translation: DAA01953.1.
AK045746 mRNA. Translation: BAC32478.1.
CCDSiCCDS26487.1.
RefSeqiNP_780549.1. NM_175340.4.
UniGeneiMm.25593.

Genome annotation databases

EnsembliENSMUST00000052747; ENSMUSP00000054990; ENSMUSG00000044231.
GeneIDi105193.
KEGGimmu:105193.
UCSCiuc007qhp.2. mouse.

Cross-referencesi

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
BK001499 mRNA. Translation: DAA01953.1.
AK045746 mRNA. Translation: BAC32478.1.
CCDSiCCDS26487.1.
RefSeqiNP_780549.1. NM_175340.4.
UniGeneiMm.25593.

3D structure databases

ProteinModelPortaliQ8BR37.
SMRiQ8BR37. Positions 25-98.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi222784. 2 interactions.
STRINGi10090.ENSMUSP00000054990.

Proteomic databases

MaxQBiQ8BR37.
PaxDbiQ8BR37.
PRIDEiQ8BR37.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENSMUST00000052747; ENSMUSP00000054990; ENSMUSG00000044231.
GeneIDi105193.
KEGGimmu:105193.
UCSCiuc007qhp.2. mouse.

Organism-specific databases

CTDi378884.
MGIiMGI:2145264. Nhlrc1.

Phylogenomic databases

eggNOGiENOG410ITF2. Eukaryota.
ENOG410ZMHC. LUCA.
GeneTreeiENSGT00730000111361.
HOGENOMiHOG000113780.
HOVERGENiHBG052617.
InParanoidiQ8BR37.
KOiK10602.
OMAiPRNLPCG.
OrthoDBiEOG7VX8W6.
PhylomeDBiQ8BR37.
TreeFamiTF331018.

Enzyme and pathway databases

UniPathwayiUPA00143.
ReactomeiR-MMU-3322077. Glycogen synthesis.

Miscellaneous databases

NextBioi357484.
PROiQ8BR37.
SOURCEiSearch...

Gene expression databases

BgeeiQ8BR37.
CleanExiMM_NHLRC1.
ExpressionAtlasiQ8BR37. baseline and differential.
GenevisibleiQ8BR37. MM.

Family and domain databases

Gene3Di2.120.10.30. 1 hit.
3.30.40.10. 1 hit.
InterProiIPR011042. 6-blade_b-propeller_TolB-like.
IPR013017. NHL_repeat_subgr.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamiPF14634. zf-RING_5. 1 hit.
[Graphical view]
SMARTiSM00184. RING. 1 hit.
[Graphical view]
PROSITEiPS51125. NHL. 6 hits.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetiSearch...

Publicationsi

« Hide 'large scale' publications
  1. Cited for: NUCLEOTIDE SEQUENCE [MRNA].
  2. "The transcriptional landscape of the mammalian genome."
    Carninci P., Kasukawa T., Katayama S., Gough J., Frith M.C., Maeda N., Oyama R., Ravasi T., Lenhard B., Wells C., Kodzius R., Shimokawa K., Bajic V.B., Brenner S.E., Batalov S., Forrest A.R., Zavolan M., Davis M.J.
    , Wilming L.G., Aidinis V., Allen J.E., Ambesi-Impiombato A., Apweiler R., Aturaliya R.N., Bailey T.L., Bansal M., Baxter L., Beisel K.W., Bersano T., Bono H., Chalk A.M., Chiu K.P., Choudhary V., Christoffels A., Clutterbuck D.R., Crowe M.L., Dalla E., Dalrymple B.P., de Bono B., Della Gatta G., di Bernardo D., Down T., Engstrom P., Fagiolini M., Faulkner G., Fletcher C.F., Fukushima T., Furuno M., Futaki S., Gariboldi M., Georgii-Hemming P., Gingeras T.R., Gojobori T., Green R.E., Gustincich S., Harbers M., Hayashi Y., Hensch T.K., Hirokawa N., Hill D., Huminiecki L., Iacono M., Ikeo K., Iwama A., Ishikawa T., Jakt M., Kanapin A., Katoh M., Kawasawa Y., Kelso J., Kitamura H., Kitano H., Kollias G., Krishnan S.P., Kruger A., Kummerfeld S.K., Kurochkin I.V., Lareau L.F., Lazarevic D., Lipovich L., Liu J., Liuni S., McWilliam S., Madan Babu M., Madera M., Marchionni L., Matsuda H., Matsuzawa S., Miki H., Mignone F., Miyake S., Morris K., Mottagui-Tabar S., Mulder N., Nakano N., Nakauchi H., Ng P., Nilsson R., Nishiguchi S., Nishikawa S., Nori F., Ohara O., Okazaki Y., Orlando V., Pang K.C., Pavan W.J., Pavesi G., Pesole G., Petrovsky N., Piazza S., Reed J., Reid J.F., Ring B.Z., Ringwald M., Rost B., Ruan Y., Salzberg S.L., Sandelin A., Schneider C., Schoenbach C., Sekiguchi K., Semple C.A., Seno S., Sessa L., Sheng Y., Shibata Y., Shimada H., Shimada K., Silva D., Sinclair B., Sperling S., Stupka E., Sugiura K., Sultana R., Takenaka Y., Taki K., Tammoja K., Tan S.L., Tang S., Taylor M.S., Tegner J., Teichmann S.A., Ueda H.R., van Nimwegen E., Verardo R., Wei C.L., Yagi K., Yamanishi H., Zabarovsky E., Zhu S., Zimmer A., Hide W., Bult C., Grimmond S.M., Teasdale R.D., Liu E.T., Brusic V., Quackenbush J., Wahlestedt C., Mattick J.S., Hume D.A., Kai C., Sasaki D., Tomaru Y., Fukuda S., Kanamori-Katayama M., Suzuki M., Aoki J., Arakawa T., Iida J., Imamura K., Itoh M., Kato T., Kawaji H., Kawagashira N., Kawashima T., Kojima M., Kondo S., Konno H., Nakano K., Ninomiya N., Nishio T., Okada M., Plessy C., Shibata K., Shiraki T., Suzuki S., Tagami M., Waki K., Watahiki A., Okamura-Oho Y., Suzuki H., Kawai J., Hayashizaki Y.
    Science 309:1559-1563(2005) [PubMed] [Europe PMC] [Abstract]
    Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA].
    Strain: C57BL/6J.
    Tissue: Brain.
  3. "The malin-laforin complex suppresses the cellular toxicity of misfolded proteins by promoting their degradation through the ubiquitin-proteasome system."
    Garyali P., Siwach P., Singh P.K., Puri R., Mittal S., Sengupta S., Parihar R., Ganesh S.
    Hum. Mol. Genet. 18:688-700(2009) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, COMPLEX FORMATION WITH EPM2A AND HSP70.
  4. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  5. Cited for: FUNCTION, DISRUPTION PHENOTYPE.
  6. "Increased laforin and laforin binding to glycogen underlie Lafora body formation in malin-deficient Lafora disease."
    Tiberia E., Turnbull J., Wang T., Ruggieri A., Zhao X.C., Pencea N., Israelian J., Wang Y., Ackerley C.A., Wang P., Liu Y., Minassian B.A.
    J. Biol. Chem. 287:25650-25659(2012) [PubMed] [Europe PMC] [Abstract]
    Cited for: FUNCTION, DISRUPTION PHENOTYPE.

Entry informationi

Entry nameiNHLC1_MOUSE
AccessioniPrimary (citable) accession number: Q8BR37
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: March 1, 2003
Last modified: February 17, 2016
This is version 106 of the entry and version 1 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. MGD cross-references
    Mouse Genome Database (MGD) cross-references in UniProtKB/Swiss-Prot
  2. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  3. SIMILARITY comments
    Index of protein domains and families

Similar proteinsi

Links to similar proteins from the UniProt Reference Clusters (UniRef) at 100%, 90% and 50% sequence identity:
100%UniRef100 combines identical sequences and sub-fragments with 11 or more residues from any organism into one UniRef entry.
90%UniRef90 is built by clustering UniRef100 sequences that have at least 90% sequence identity to, and 80% overlap with, the longest sequence (a.k.a seed sequence).
50%UniRef50 is built by clustering UniRef90 seed sequences that have at least 50% sequence identity to, and 80% overlap with, the longest sequence in the cluster.