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Protein

E3 ubiquitin-protein ligase NHLRC1

Gene

NHLRC1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: Annotation score: 5 out of 5-Experimental evidence at protein 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.6 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)DescriptionActionsGraphical viewLength
Zinc fingeri26 – 72RING-typePROSITE-ProRule annotationAdd BLAST47

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

BioCyciZFISH:G66-33129-MONOMER.
ReactomeiR-HSA-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
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi
  • UP000005640 Componenti: Chromosome 6

Organism-specific databases

HGNCiHGNC:21576. NHLRC1.

Subcellular locationi

GO - Cellular componenti

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

Keywords - Cellular componenti

Endoplasmic reticulum, Nucleus

Pathology & Biotechi

Involvement in diseasei

Epilepsy, progressive myoclonic 2 (EPM2)5 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionAn autosomal recessive and severe form of adolescent-onset progressive epilepsy. Typically, as seizures increase in frequency, cognitive function declines towards dementia, and affected individuals die usually within 10 years after onset. EPM2 occurs worldwide, but it is particularly common in the mediterranean countries of southern Europe and northern Africa, in southern India and in the Middle East. At the cellular level, it is characterized by accumulation of starch-like polyglucosans called Lafora bodies (LBs) that are most abundant in organs with the highest glucose metabolism: brain, heart, liver and skeletal muscle. Among other conditions involving polyglucosans, EPM2 is unique in that the inclusions are in neuronal dendrites but not axons and the forming polyglucosan fibrils are associated with the endoplasmic reticulum.
See also OMIM:254780
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04638722S → R in EPM2; does not significantly alters the subcellular location as compared to the wild-type. 1 Publication1
Natural variantiVAR_01948226C → S in EPM2. 1 PublicationCorresponds to variant rs28940575dbSNPEnsembl.1
Natural variantiVAR_01948333F → S in EPM2. 1 PublicationCorresponds to variant rs757759398dbSNPEnsembl.1
Natural variantiVAR_07079346C → Y in EPM2; compound heterozygote with A-69; loss of interaction with EPM2A; increased levels of PPP1R3C and glycogen. 1 Publication1
Natural variantiVAR_04638867E → Q in EPM2. 1 PublicationCorresponds to variant rs779507031dbSNPEnsembl.1
Natural variantiVAR_04638968C → Y in EPM2. 1 Publication1
Natural variantiVAR_01948469P → A in EPM2; compound heterozygote with Y-46; severely reduced interaction with EPM2A; increased levels of PPP1R3C and glycogen. 2 PublicationsCorresponds to variant rs28940576dbSNPEnsembl.1
Natural variantiVAR_01948587L → P in EPM2. 1 Publication1
Natural variantiVAR_046390126L → P in EPM2; the mutant protein targeted exclusively nucleus as compared to predominantly cytoplasmic and partially nuclear localization of the wild-type protein. 1 Publication1
Natural variantiVAR_019487146D → N in EPM2; compound heterozygote with P-261; severely reduced interaction with EPM2A; increased levels of PPP1R3C and glycogen. 2 PublicationsCorresponds to variant rs769301934dbSNPEnsembl.1
Natural variantiVAR_046391153I → M in EPM2. 1 Publication1
Natural variantiVAR_046392160C → R in EPM2. 1 PublicationCorresponds to variant rs200595273dbSNPEnsembl.1
Natural variantiVAR_046393198I → N in EPM2. 1 PublicationCorresponds to variant rs121917876dbSNPEnsembl.1
Natural variantiVAR_046394219W → R in EPM2. 1 Publication1
Natural variantiVAR_046395233D → A in EPM2. 1 Publication1
Natural variantiVAR_046396245D → N in EPM2. 1 Publication1
Natural variantiVAR_046397253R → K in EPM2. 1 Publication1
Natural variantiVAR_070794261L → P in EPM2; compound heterozygote with N-146; loss of interaction with EPM2A; increased levels of PPP1R3C and glycogen. 1 Publication1
Natural variantiVAR_046398264P → H in EPM2. 1 Publication1
Natural variantiVAR_046399279L → P in EPM2; significantly alters the distribution of the protein; a great majority of cells expressing the mutant form formed perinuclear inclusion when compared with the wild-type form. 1 Publication1
Natural variantiVAR_046400294 – 295Missing in EPM2. 1 Publication2
Natural variantiVAR_019488302Q → P in EPM2; loss of interaction with EPM2A. 2 PublicationsCorresponds to variant rs757858146dbSNPEnsembl.1
Natural variantiVAR_046401308D → A in EPM2. 1 PublicationCorresponds to variant rs137852859dbSNPEnsembl.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi280E → K: Loss of interaction with EP2MA. 1 Publication1

Keywords - Diseasei

Disease mutation, Epilepsy

Organism-specific databases

DisGeNETi378884.
MalaCardsiNHLRC1.
MIMi254780. phenotype.
OpenTargetsiENSG00000187566.
Orphaneti501. Lafora disease.
PharmGKBiPA134916338.

Polymorphism and mutation databases

BioMutaiNHLRC1.
DMDMi50400890.

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000559801 – 395E3 ubiquitin-protein ligase NHLRC1Add BLAST395

Proteomic databases

PaxDbiQ6VVB1.
PeptideAtlasiQ6VVB1.
PRIDEiQ6VVB1.

PTM databases

iPTMnetiQ6VVB1.
PhosphoSitePlusiQ6VVB1.

Expressioni

Tissue specificityi

Expressed in brain, cerebellum, spinal cord, medulla, heart, liver, skeletal muscle and pancreas.1 Publication

Gene expression databases

BgeeiENSG00000187566.
CleanExiHS_NHLRC1.

Organism-specific databases

HPAiHPA066030.

Interactioni

Subunit structurei

Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70. Interacts with PRDM8 (PubMed:22961547).4 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
EPM2AO952787EBI-6426628,EBI-2506661
Epm2aQ9WUA512EBI-6426628,EBI-1040928From a different organism.

Protein-protein interaction databases

BioGridi132073. 16 interactors.
IntActiQ6VVB1. 13 interactors.
MINTiMINT-8374086.
STRINGi9606.ENSP00000345464.

Structurei

3D structure databases

ProteinModelPortaliQ6VVB1.
SMRiQ6VVB1.
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati113 – 157NHL 1Add BLAST45
Repeati161 – 204NHL 2Add BLAST44
Repeati205 – 245NHL 3Add BLAST41
Repeati248 – 300NHL 4Add BLAST53
Repeati301 – 349NHL 5Add BLAST49
Repeati350 – 393NHL 6Add BLAST44

Domaini

The RING domain is essential for ubiquitin E3 ligase activity.1 Publication

Sequence similaritiesi

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

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri26 – 72RING-typePROSITE-ProRule annotationAdd BLAST47

Keywords - Domaini

Repeat, Zinc-finger

Phylogenomic databases

eggNOGiENOG410ITF2. Eukaryota.
ENOG410ZMHC. LUCA.
GeneTreeiENSGT00730000111361.
HOGENOMiHOG000113780.
HOVERGENiHBG052617.
InParanoidiQ6VVB1.
KOiK10602.
OMAiPRNLPCG.
OrthoDBiEOG091G08MU.
PhylomeDBiQ6VVB1.
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.

Q6VVB1-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MAAEASESGP ALHELMREAE ISLLECKVCF EKFGHRQQRR PRNLSCGHVV
60 70 80 90 100
CLACVAALAH PRTLALECPF CRRACRGCDT SDCLPVLHLI ELLGSALRQS
110 120 130 140 150
PAAHRAAPSA PGALTCHHTF GGWGTLVNPT GLALCPKTGR VVVVHDGRRR
160 170 180 190 200
VKIFDSGGGC AHQFGEKGDA AQDIRYPVDV TITNDCHVVV TDAGDRSIKV
210 220 230 240 250
FDFFGQIKLV IGGQFSLPWG VETTPQNGIV VTDAEAGSLH LLDVDFAEGV
260 270 280 290 300
LRRTERLQAH LCNPRGVAVS WLTGAIAVLE HPLALGTGVC STRVKVFSSS
310 320 330 340 350
MQLVGQVDTF GLSLYFPSKI TASAVTFDHQ GNVIVADTSG PAILCLGKPE
360 370 380 390
EFPVPKPMVT HGLSHPVALT FTKENSLLVL DTASHSIKVY KVDWG
Length:395
Mass (Da):42,293
Last modified:July 19, 2004 - v2
Checksum:i3E8339D00165FBED
GO

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_04638722S → R in EPM2; does not significantly alters the subcellular location as compared to the wild-type. 1 Publication1
Natural variantiVAR_01948226C → S in EPM2. 1 PublicationCorresponds to variant rs28940575dbSNPEnsembl.1
Natural variantiVAR_01948333F → S in EPM2. 1 PublicationCorresponds to variant rs757759398dbSNPEnsembl.1
Natural variantiVAR_07079346C → Y in EPM2; compound heterozygote with A-69; loss of interaction with EPM2A; increased levels of PPP1R3C and glycogen. 1 Publication1
Natural variantiVAR_04638867E → Q in EPM2. 1 PublicationCorresponds to variant rs779507031dbSNPEnsembl.1
Natural variantiVAR_04638968C → Y in EPM2. 1 Publication1
Natural variantiVAR_01948469P → A in EPM2; compound heterozygote with Y-46; severely reduced interaction with EPM2A; increased levels of PPP1R3C and glycogen. 2 PublicationsCorresponds to variant rs28940576dbSNPEnsembl.1
Natural variantiVAR_01948587L → P in EPM2. 1 Publication1
Natural variantiVAR_019486111P → L Common polymorphism. 3 PublicationsCorresponds to variant rs10949483dbSNPEnsembl.1
Natural variantiVAR_046390126L → P in EPM2; the mutant protein targeted exclusively nucleus as compared to predominantly cytoplasmic and partially nuclear localization of the wild-type protein. 1 Publication1
Natural variantiVAR_019487146D → N in EPM2; compound heterozygote with P-261; severely reduced interaction with EPM2A; increased levels of PPP1R3C and glycogen. 2 PublicationsCorresponds to variant rs769301934dbSNPEnsembl.1
Natural variantiVAR_046391153I → M in EPM2. 1 Publication1
Natural variantiVAR_046392160C → R in EPM2. 1 PublicationCorresponds to variant rs200595273dbSNPEnsembl.1
Natural variantiVAR_046393198I → N in EPM2. 1 PublicationCorresponds to variant rs121917876dbSNPEnsembl.1
Natural variantiVAR_046394219W → R in EPM2. 1 Publication1
Natural variantiVAR_046395233D → A in EPM2. 1 Publication1
Natural variantiVAR_046396245D → N in EPM2. 1 Publication1
Natural variantiVAR_046397253R → K in EPM2. 1 Publication1
Natural variantiVAR_070794261L → P in EPM2; compound heterozygote with N-146; loss of interaction with EPM2A; increased levels of PPP1R3C and glycogen. 1 Publication1
Natural variantiVAR_046398264P → H in EPM2. 1 Publication1
Natural variantiVAR_046399279L → P in EPM2; significantly alters the distribution of the protein; a great majority of cells expressing the mutant form formed perinuclear inclusion when compared with the wild-type form. 1 Publication1
Natural variantiVAR_046400294 – 295Missing in EPM2. 1 Publication2
Natural variantiVAR_019488302Q → P in EPM2; loss of interaction with EPM2A. 2 PublicationsCorresponds to variant rs757858146dbSNPEnsembl.1
Natural variantiVAR_046401308D → A in EPM2. 1 PublicationCorresponds to variant rs137852859dbSNPEnsembl.1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY324850 mRNA. Translation: AAQ19671.1.
AL589723 Genomic DNA. Translation: CAH71232.1.
BC103888 mRNA. Translation: AAI03889.1.
BC103889 mRNA. Translation: AAI03890.1.
BC103890 mRNA. Translation: AAI03891.1.
BK001510 mRNA. Translation: DAA01954.1.
CCDSiCCDS4542.1.
RefSeqiNP_940988.2. NM_198586.2.
UniGeneiHs.348351.

Genome annotation databases

EnsembliENST00000340650; ENSP00000345464; ENSG00000187566.
GeneIDi378884.
KEGGihsa:378884.
UCSCiuc003ncl.2. human.

Keywords - Coding sequence diversityi

Polymorphism

Cross-referencesi

Web resourcesi

The Lafora progressive myoclonus epilepsy mutation and polymorphism database

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY324850 mRNA. Translation: AAQ19671.1.
AL589723 Genomic DNA. Translation: CAH71232.1.
BC103888 mRNA. Translation: AAI03889.1.
BC103889 mRNA. Translation: AAI03890.1.
BC103890 mRNA. Translation: AAI03891.1.
BK001510 mRNA. Translation: DAA01954.1.
CCDSiCCDS4542.1.
RefSeqiNP_940988.2. NM_198586.2.
UniGeneiHs.348351.

3D structure databases

ProteinModelPortaliQ6VVB1.
SMRiQ6VVB1.
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi132073. 16 interactors.
IntActiQ6VVB1. 13 interactors.
MINTiMINT-8374086.
STRINGi9606.ENSP00000345464.

PTM databases

iPTMnetiQ6VVB1.
PhosphoSitePlusiQ6VVB1.

Polymorphism and mutation databases

BioMutaiNHLRC1.
DMDMi50400890.

Proteomic databases

PaxDbiQ6VVB1.
PeptideAtlasiQ6VVB1.
PRIDEiQ6VVB1.

Protocols and materials databases

Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000340650; ENSP00000345464; ENSG00000187566.
GeneIDi378884.
KEGGihsa:378884.
UCSCiuc003ncl.2. human.

Organism-specific databases

CTDi378884.
DisGeNETi378884.
GeneCardsiNHLRC1.
GeneReviewsiNHLRC1.
HGNCiHGNC:21576. NHLRC1.
HPAiHPA066030.
MalaCardsiNHLRC1.
MIMi254780. phenotype.
608072. gene.
neXtProtiNX_Q6VVB1.
OpenTargetsiENSG00000187566.
Orphaneti501. Lafora disease.
PharmGKBiPA134916338.
GenAtlasiSearch...

Phylogenomic databases

eggNOGiENOG410ITF2. Eukaryota.
ENOG410ZMHC. LUCA.
GeneTreeiENSGT00730000111361.
HOGENOMiHOG000113780.
HOVERGENiHBG052617.
InParanoidiQ6VVB1.
KOiK10602.
OMAiPRNLPCG.
OrthoDBiEOG091G08MU.
PhylomeDBiQ6VVB1.
TreeFamiTF331018.

Enzyme and pathway databases

UniPathwayiUPA00143.
BioCyciZFISH:G66-33129-MONOMER.
ReactomeiR-HSA-3322077. Glycogen synthesis.

Miscellaneous databases

GeneWikiiNHLRC1.
GenomeRNAii378884.
PROiQ6VVB1.
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000187566.
CleanExiHS_NHLRC1.

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...

Entry informationi

Entry nameiNHLC1_HUMAN
AccessioniPrimary (citable) accession number: Q6VVB1
Secondary accession number(s): Q3SYB1, Q5VUK7, Q6IMH1
Entry historyi
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: July 19, 2004
Last modified: November 30, 2016
This is version 123 of the entry and version 2 of the sequence. [Complete history]
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

Miscellaneousi

Keywords - Technical termi

Complete proteome, Reference proteome

Documents

  1. Human chromosome 6
    Human chromosome 6: entries, gene names and cross-references to MIM
  2. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  3. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  4. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  5. PATHWAY comments
    Index of metabolic and biosynthesis pathways
  6. 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.