Q6VVB1 (NHLC1_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	395 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E3 ubiquitin-protein ligase which 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 PPP1R3C/PTG in a laforin-dependent manner, and targets it for proteasome-dependent degradation and this degradation decreases glycogen accumulation. Polyubiquitinates EPM2A/laforin and ubiquitinates AGL and targets them for proteasome-dependent degradation. Ref.3 Ref.4 Ref.5 Ref.6
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.3 Ref.4
Subcellular location	Endoplasmic reticulum. Nucleus. Note: Localizes at the endoplasmic reticulum and, to a lesser extent, in the nucleus. Ref.1 Ref.4
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.3
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.3 Ref.6 Ref.8 Ref.9 Ref.10
Sequence similarities	Contains 6 NHL repeats. Contains 1 RING-type zinc finger.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Endoplasmic reticulum Nucleus
Coding sequence diversity	Polymorphism
Disease	Disease mutation Epilepsy
Domain	Repeat Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	positive regulation of protein ubiquitination Inferred from electronic annotation. Source: Compara proteasomal ubiquitin-dependent protein catabolic process Inferred from direct assay Ref.3. Source: UniProtKB protein polyubiquitination Inferred from direct assay Ref.3. Source: UniProtKB
Cellular_component	endoplasmic reticulum Inferred from electronic annotation. Source: UniProtKB-SubCell nucleus Inferred from direct assay Ref.4. Source: UniProtKB perinuclear region of cytoplasm Inferred from electronic annotation. Source: Compara
Molecular_function	ubiquitin-protein ligase activity Inferred from direct assay Ref.3Ref.5. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 395	395	E3 ubiquitin-protein ligase NHLRC1		PRO_0000055980
Regions
	Repeat	113 – 157	45	NHL 1
	Repeat	161 – 204	44	NHL 2
	Repeat	205 – 245	41	NHL 3
	Repeat	248 – 300	53	NHL 4
	Repeat	301 – 349	49	NHL 5
	Repeat	350 – 393	44	NHL 6
	Zinc finger	26 – 72	47	RING-type
Natural variations
	Natural variant	22	1	S → R in EPM2; does not significantly alters the subcellular location as compared to the wild-type. Ref.10		VAR_046387
	Natural variant	26	1	C → S in EPM2. Ref.1 Corresponds to variant rs28940575 [ dbSNP | Ensembl ].		VAR_019482
	Natural variant	33	1	F → S in EPM2. Ref.1		VAR_019483
	Natural variant	67	1	E → Q in EPM2. Ref.9		VAR_046388
	Natural variant	68	1	C → Y in EPM2. Ref.9		VAR_046389
	Natural variant	69	1	P → A in EPM2. Ref.1 Corresponds to variant rs28940576 [ dbSNP | Ensembl ].		VAR_019484
	Natural variant	87	1	L → P in EPM2. Ref.1		VAR_019485
	Natural variant	111	1	P → L Common polymorphism. Ref.1 Ref.7 Ref.8 Corresponds to variant rs10949483 [ dbSNP | Ensembl ].		VAR_019486
	Natural variant	126	1	L → P in EPM2; the mutant protein targeted exclusively nucleus as compared to predominantly cytoplasmic and partially nuclear localization of the wild-type protein. Ref.10		VAR_046390
	Natural variant	146	1	D → N in EPM2. Ref.1		VAR_019487
	Natural variant	153	1	I → M in EPM2. Ref.8		VAR_046391
	Natural variant	160	1	C → R in EPM2. Ref.8		VAR_046392
	Natural variant	198	1	I → N in EPM2. Ref.9		VAR_046393
	Natural variant	219	1	W → R in EPM2. Ref.8		VAR_046394
	Natural variant	233	1	D → A in EPM2. Ref.9		VAR_046395
	Natural variant	245	1	D → N in EPM2. Ref.8		VAR_046396
	Natural variant	253	1	R → K in EPM2. Ref.8		VAR_046397
	Natural variant	264	1	P → H in EPM2. Ref.9		VAR_046398
	Natural variant	279	1	L → 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.10		VAR_046399
	Natural variant	294 – 295	2	Missing in EPM2.		VAR_046400
	Natural variant	302	1	Q → P in EPM2; loss of interaction with EPM2A. Ref.1 Ref.3		VAR_019488
	Natural variant	308	1	D → A in EPM2. Ref.9		VAR_046401
Experimental info
	Mutagenesis	280	1	E → K: Loss of interaction with EP2MA. Ref.3

Sequences

	Sequence		Length	Mass (Da)
	Q6VVB1 [UniParc]. Last modified July 19, 2004. Version 2. Checksum: 3E8339D00165FBED	FASTA	395	42,293
	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

References

	« Hide 'large scale' referencesShow '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. , 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]	"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.
[4]	"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.
[5]	"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.
[6]	"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.
[7]	"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.
[8]	"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.
[9]	"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.
[10]	"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.
+	Additional computationally mapped references.

Web resources

The Lafora progressive myoclonus epilepsy mutation and polymorphism database

GeneReviews

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.
IPI	IPI00440247.
RefSeq	NP_940988.2. NM_198586.2.
UniGene	Hs.348351.
3D structure databases
ProteinModelPortal	Q6VVB1.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q6VVB1. 1 interaction.
STRING	9606.ENSP00000345464.
Polymorphism databases
DMDM	50400890.
Proteomic databases
PaxDb	Q6VVB1.
PRIDE	Q6VVB1.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000340650; ENSP00000345464; ENSG00000187566.
GeneID	378884.
KEGG	hsa:378884.
UCSC	uc003ncl.1. human.
Organism-specific databases
CTD	378884.
GeneCards	GC06M018065.
HGNC	HGNC:21576. NHLRC1.
MIM	254780. phenotype. 608072. gene.
neXtProt	NX_Q6VVB1.
Orphanet	501. Lafora disease.
PharmGKB	PA134916338.
GenAtlas	Search...
Phylogenomic databases
eggNOG	NOG255948.
HOGENOM	HOG000113780.
HOVERGEN	HBG052617.
InParanoid	Q6VVB1.
KO	K10602.
OMA	PRNLPCG.
OrthoDB	EOG44QT1H.
Enzyme and pathway databases
UniPathway	UPA00143.
Gene expression databases
Bgee	Q6VVB1.
CleanEx	HS_NHLRC1.
Genevestigator	Q6VVB1.
Family and domain databases
Gene3D	2.120.10.30. 1 hit. 3.30.40.10. 1 hit.
InterPro	IPR011042. 6-blade_b-propeller_TolB-like. IPR013017. NHL_repeat_subgr. IPR001841. Znf_RING. IPR013083. Znf_RING/FYVE/PHD. IPR017907. Znf_RING_CS. [Graphical view]
Pfam	PF13639. zf-RING_2. 1 hit. [Graphical view]
SMART	SM00184. RING. 1 hit. [Graphical view]
PROSITE	PS51125. NHL. 6 hits. PS00518. ZF_RING_1. 1 hit. PS50089. ZF_RING_2. 1 hit. [Graphical view]
ProtoNet	Search...
Other
GenomeRNAi	378884.
NextBio	100856.
SOURCE	Search...

Entry information

Entry name

NHLC1_HUMAN

Accession

Primary (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:	May 1, 2013
This is version 87 of the entry and version 2 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any 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.