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Q6VVB1 (NHLC1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified April 16, 2014. Version 97. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (6) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Interactions·Sequence annotation·Sequences·References·Web links·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase NHLRC1

EC=6.3.2.-
Alternative name(s):
Malin
NHL repeat-containing protein 1
Gene names
Name:NHLRC1
Synonyms:EPM2B
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length395 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

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. Ref.4 Ref.5 Ref.6 Ref.7 Ref.8 Ref.12

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Interacts with AGL. Interacts (via the NHL repeats) with EPM2A/laforin. Forms a complex with EPM2A/laforin and HSP70. Ref.4 Ref.5 Ref.12

Subcellular location

Endoplasmic reticulum. Nucleus. Note: Localizes at the endoplasmic reticulum and, to a lesser extent, in the nucleus. Ref.1 Ref.5 Ref.12

Tissue specificity

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

Domain

The RING domain is essential for ubiquitin E3 ligase activity. Ref.4

Involvement in disease

Epilepsy, progressive myoclonic 2 (EPM2) [MIM:254780]: An 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.
Note: The disease is caused by mutations affecting the gene represented in this entry. Ref.1 Ref.4 Ref.7 Ref.9 Ref.10 Ref.11 Ref.12

Sequence similarities

Contains 6 NHL repeats.

Contains 1 RING-type zinc finger.

Binary interactions

With

Entry

#Exp.

IntAct

Notes

Epm2aQ9WUA512EBI-6426628,EBI-1040928From a different organism.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 395395E3 ubiquitin-protein ligase NHLRC1
PRO_0000055980

Regions

Repeat113 – 15745NHL 1
Repeat161 – 20444NHL 2
Repeat205 – 24541NHL 3
Repeat248 – 30053NHL 4
Repeat301 – 34949NHL 5
Repeat350 – 39344NHL 6
Zinc finger26 – 7247RING-type

Natural variations

Natural variant221S → R in EPM2; does not significantly alters the subcellular location as compared to the wild-type. Ref.11
VAR_046387
Natural variant261C → S in EPM2. Ref.1
Corresponds to variant rs28940575 [ dbSNP | Ensembl ].
VAR_019482
Natural variant331F → S in EPM2. Ref.1
VAR_019483
Natural variant461C → Y in EPM2; loss of interaction with EPM2A and increased levels of PPP1R3C and glycogen; compound heterozygote with A-69. Ref.12
VAR_070793
Natural variant671E → Q in EPM2. Ref.10
VAR_046388
Natural variant681C → Y in EPM2. Ref.10
VAR_046389
Natural variant691P → A in EPM2; severely reduced interaction with EPM2A and increased levels of PPP1R3C and glycogen; in one patient compound heterozygote with Y-46. Ref.1 Ref.12
Corresponds to variant rs28940576 [ dbSNP | Ensembl ].
VAR_019484
Natural variant871L → P in EPM2. Ref.1
VAR_019485
Natural variant1111P → L Common polymorphism. Ref.1 Ref.3 Ref.9
Corresponds to variant rs10949483 [ dbSNP | Ensembl ].
VAR_019486
Natural variant1261L → P in EPM2; the mutant protein targeted exclusively nucleus as compared to predominantly cytoplasmic and partially nuclear localization of the wild-type protein. Ref.11
VAR_046390
Natural variant1461D → N in EPM2; severely reduced interaction with EPM2A and increased levels of PPP1R3C and glycogen; in one patient compound heterozygote with P-261. Ref.1 Ref.12
VAR_019487
Natural variant1531I → M in EPM2. Ref.9
VAR_046391
Natural variant1601C → R in EPM2. Ref.9
Corresponds to variant rs200595273 [ dbSNP | Ensembl ].
VAR_046392
Natural variant1981I → N in EPM2. Ref.10
VAR_046393
Natural variant2191W → R in EPM2. Ref.9
VAR_046394
Natural variant2331D → A in EPM2. Ref.10
VAR_046395
Natural variant2451D → N in EPM2. Ref.9
VAR_046396
Natural variant2531R → K in EPM2. Ref.9
VAR_046397
Natural variant2611L → P in EPM2; loss of interaction with EPM2A and increased levels of PPP1R3C and glycogen; compound heterozygote with N-146. Ref.12
VAR_070794
Natural variant2641P → H in EPM2. Ref.10
VAR_046398
Natural variant2791L → 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. Ref.11
VAR_046399
Natural variant294 – 2952Missing in EPM2.
VAR_046400
Natural variant3021Q → P in EPM2; loss of interaction with EPM2A. Ref.1 Ref.4
VAR_019488
Natural variant3081D → A in EPM2. Ref.10
VAR_046401

Experimental info

Mutagenesis2801E → K: Loss of interaction with EP2MA. Ref.4

Sequences

Sequence LengthMass (Da)Tools
Q6VVB1 [UniParc].

Last modified July 19, 2004. Version 2.
Checksum: 3E8339D00165FBED

FASTA39542,293
        10         20         30         40         50         60 
MAAEASESGP ALHELMREAE ISLLECKVCF EKFGHRQQRR PRNLSCGHVV CLACVAALAH 

        70         80         90        100        110        120 
PRTLALECPF CRRACRGCDT SDCLPVLHLI ELLGSALRQS PAAHRAAPSA PGALTCHHTF 

       130        140        150        160        170        180 
GGWGTLVNPT GLALCPKTGR VVVVHDGRRR VKIFDSGGGC AHQFGEKGDA AQDIRYPVDV 

       190        200        210        220        230        240 
TITNDCHVVV TDAGDRSIKV FDFFGQIKLV IGGQFSLPWG VETTPQNGIV VTDAEAGSLH 

       250        260        270        280        290        300 
LLDVDFAEGV LRRTERLQAH LCNPRGVAVS WLTGAIAVLE HPLALGTGVC STRVKVFSSS 

       310        320        330        340        350        360 
MQLVGQVDTF GLSLYFPSKI TASAVTFDHQ GNVIVADTSG PAILCLGKPE EFPVPKPMVT 

       370        380        390 
HGLSHPVALT FTKENSLLVL DTASHSIKVY KVDWG 

« Hide

References

« Hide 'large scale' references
[1]"Mutations in NHLRC1 cause progressive myoclonus epilepsy."
Chan E.M., Young E.J., Ianzano L., Munteanu I., Zhao X., Christopoulos C.C., Avanzini G., Elia M., Ackerley C.A., Jovic N.J., Bohlega S., Andermann E., Rouleau G.A., Delgado-Escueta A.V., Minassian B.A., Scherer S.W.
Nat. Genet. 35:125-127(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA], SUBCELLULAR LOCATION, TISSUE SPECIFICITY, VARIANTS EPM2 SER-26; SER-33; ALA-69; PRO-87; ASN-146 AND PRO-302, VARIANT LEU-111.
[2]"The DNA sequence and analysis of human chromosome 6."
Mungall A.J., Palmer S.A., Sims S.K., Edwards C.A., Ashurst J.L., Wilming L., Jones M.C., Horton R., Hunt S.E., Scott C.E., Gilbert J.G.R., Clamp M.E., Bethel G., Milne S., Ainscough R., Almeida J.P., Ambrose K.D., Andrews T.D. expand/collapse author list , Ashwell R.I.S., Babbage A.K., Bagguley C.L., Bailey J., Banerjee R., Barker D.J., Barlow K.F., Bates K., Beare D.M., Beasley H., Beasley O., Bird C.P., Blakey S.E., Bray-Allen S., Brook J., Brown A.J., Brown J.Y., Burford D.C., Burrill W., Burton J., Carder C., Carter N.P., Chapman J.C., Clark S.Y., Clark G., Clee C.M., Clegg S., Cobley V., Collier R.E., Collins J.E., Colman L.K., Corby N.R., Coville G.J., Culley K.M., Dhami P., Davies J., Dunn M., Earthrowl M.E., Ellington A.E., Evans K.A., Faulkner L., Francis M.D., Frankish A., Frankland J., French L., Garner P., Garnett J., Ghori M.J., Gilby L.M., Gillson C.J., Glithero R.J., Grafham D.V., Grant M., Gribble S., Griffiths C., Griffiths M.N.D., Hall R., Halls K.S., Hammond S., Harley J.L., Hart E.A., Heath P.D., Heathcott R., Holmes S.J., Howden P.J., Howe K.L., Howell G.R., Huckle E., Humphray S.J., Humphries M.D., Hunt A.R., Johnson C.M., Joy A.A., Kay M., Keenan S.J., Kimberley A.M., King A., Laird G.K., Langford C., Lawlor S., Leongamornlert D.A., Leversha M., Lloyd C.R., Lloyd D.M., Loveland J.E., Lovell J., Martin S., Mashreghi-Mohammadi M., Maslen G.L., Matthews L., McCann O.T., McLaren S.J., McLay K., McMurray A., Moore M.J.F., Mullikin J.C., Niblett D., Nickerson T., Novik K.L., Oliver K., Overton-Larty E.K., Parker A., Patel R., Pearce A.V., Peck A.I., Phillimore B.J.C.T., Phillips S., Plumb R.W., Porter K.M., Ramsey Y., Ranby S.A., Rice C.M., Ross M.T., Searle S.M., Sehra H.K., Sheridan E., Skuce C.D., Smith S., Smith M., Spraggon L., Squares S.L., Steward C.A., Sycamore N., Tamlyn-Hall G., Tester J., Theaker A.J., Thomas D.W., Thorpe A., Tracey A., Tromans A., Tubby B., Wall M., Wallis J.M., West A.P., White S.S., Whitehead S.L., Whittaker H., Wild A., Willey D.J., Wilmer T.E., Wood J.M., Wray P.W., Wyatt J.C., Young L., Younger R.M., Bentley D.R., Coulson A., Durbin R.M., Hubbard T., Sulston J.E., Dunham I., Rogers J., Beck S.
Nature 425:805-811(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[3]"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)."
The MGC Project Team
Genome Res. 14:2121-2127(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA], VARIANT LEU-111.
[4]"Insights into Lafora disease: malin is an E3 ubiquitin ligase that ubiquitinates and promotes the degradation of laforin."
Gentry M.S., Worby C.A., Dixon J.E.
Proc. Natl. Acad. Sci. U.S.A. 102:8501-8506(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH EPM2A, DOMAIN RING, CHARACTERIZATION OF VARIANT EPM2 PRO-302, MUTAGENESIS OF GLU-280.
[5]"A role for AGL ubiquitination in the glycogen storage disorders of Lafora and Cori's disease."
Cheng A., Zhang M., Gentry M.S., Worby C.A., Dixon J.E., Saltiel A.R.
Genes Dev. 21:2399-2409(2007) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH AGL.
[6]"Malin decreases glycogen accumulation by promoting the degradation of protein targeting to glycogen (PTG)."
Worby C.A., Gentry M.S., Dixon J.E.
J. Biol. Chem. 283:4069-4076(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[7]"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.
[8]"Glycogenic activity of R6, a protein phosphatase 1 regulatory subunit, is modulated by the laforin-malin complex."
Rubio-Villena C., Garcia-Gimeno M.A., Sanz P.
Int. J. Biochem. Cell Biol. 45:1479-1488(2013) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[9]"Mutations in the NHLRC1 gene are the common cause for Lafora disease in the Japanese population."
Singh S., Suzuki T., Uchiyama A., Kumada S., Moriyama N., Hirose S., Takahashi Y., Sugie H., Mizoguchi K., Inoue Y., Kimura K., Sawaishi Y., Yamakawa K., Ganesh S.
J. Hum. Genet. 50:347-352(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS EPM2 MET-153; ARG-160; ARG-219; ASN-245 AND LYS-253, VARIANT LEU-111.
[10]"Lafora disease due to EPM2B mutations: a clinical and genetic study."
Gomez-Abad C., Gomez-Garre P., Gutierrez-Delicado E., Saygi S., Michelucci R., Tassinari C.A., Rodriguez de Cordoba S., Serratosa J.M.
Neurology 64:982-986(2005) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS EPM2 GLN-67; TYR-68; ASN-198; ALA-233; HIS-264; 294-VAL-LYS-295 DEL AND ALA-308.
[11]"Lafora disease in the Indian population: EPM2A and NHLRC1 gene mutations and their impact on subcellular localization of laforin and malin."
Singh S., Satishchandra P., Shankar S.K., Ganesh S.
Hum. Mutat. 29:E1-12(2008) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS EPM2 ARG-22; PRO-126 AND PRO-279, CHARACTERIZATION OF VARIANTS EPM2 ARG-22; PRO-126 AND PRO-279.
[12]"Lafora progressive myoclonus epilepsy: NHLRC1 mutations affect glycogen metabolism."
Couarch P., Vernia S., Gourfinkel-An I., Lesca G., Gataullina S., Fedirko E., Trouillard O., Depienne C., Dulac O., Steschenko D., Leguern E., Sanz P., Baulac S.
J. Mol. Med. 89:915-925(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: VARIANTS EPM2 TYR-46; ALA-69; ASN-146 AND PRO-261, CHARACTERIZATION OF VARIANTS EPM2 TYR-46; ALA-69; ASN-146 AND PRO-261, FUNCTION, SUBCELLULAR LOCATION, INTERACTION WITH EPM2A.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
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.
RefSeqNP_940988.2. NM_198586.2.
UniGeneHs.348351.

3D structure databases

ProteinModelPortalQ6VVB1.
SMRQ6VVB1. Positions 23-76, 117-337, 360-392.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid132073. 16 interactions.
IntActQ6VVB1. 3 interactions.
MINTMINT-8374086.
STRING9606.ENSP00000345464.

Polymorphism databases

DMDM50400890.

Proteomic databases

PaxDbQ6VVB1.
PRIDEQ6VVB1.

Protocols and materials databases

StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000340650; ENSP00000345464; ENSG00000187566.
GeneID378884.
KEGGhsa:378884.
UCSCuc003ncl.1. human.

Organism-specific databases

CTD378884.
GeneCardsGC06M018065.
HGNCHGNC:21576. NHLRC1.
MIM254780. phenotype.
608072. gene.
neXtProtNX_Q6VVB1.
Orphanet501. Lafora disease.
PharmGKBPA134916338.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG255948.
HOGENOMHOG000113780.
HOVERGENHBG052617.
InParanoidQ6VVB1.
KOK10602.
OMAPRNLPCG.
OrthoDBEOG7VX8W6.
PhylomeDBQ6VVB1.
TreeFamTF331018.

Enzyme and pathway databases

ReactomeREACT_111217. Metabolism.
UniPathwayUPA00143.

Gene expression databases

BgeeQ6VVB1.
CleanExHS_NHLRC1.
GenevestigatorQ6VVB1.

Family and domain databases

Gene3D2.120.10.30. 1 hit.
3.30.40.10. 1 hit.
InterProIPR011042. 6-blade_b-propeller_TolB-like.
IPR013017. NHL_repeat_subgr.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
IPR017907. Znf_RING_CS.
[Graphical view]
PfamPF14634. zf-RING_5. 1 hit.
[Graphical view]
SMARTSM00184. RING. 1 hit.
[Graphical view]
PROSITEPS51125. NHL. 6 hits.
PS00518. ZF_RING_1. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiNHLRC1.
GenomeRNAi378884.
NextBio100856.
PROQ6VVB1.
SOURCESearch...

Entry information

Entry nameNHLC1_HUMAN
AccessionPrimary (citable) accession number: Q6VVB1
Secondary accession number(s): Q3SYB1, Q5VUK7, Q6IMH1
Entry history
Integrated into UniProtKB/Swiss-Prot: July 19, 2004
Last sequence update: July 19, 2004
Last modified: April 16, 2014
This is version 97 of the entry and version 2 of the sequence. [Complete history]
Entry statusReviewed (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.

Relevant documents

SIMILARITY comments

Index of protein domains and families

PATHWAY comments

Index of metabolic and biosynthesis pathways

MIM cross-references

Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot

Human polymorphisms and disease mutations

Index of human polymorphisms and disease mutations

Human entries with polymorphisms or disease mutations

List of human entries with polymorphisms or disease mutations

Human chromosome 6

Human chromosome 6: entries, gene names and cross-references to MIM