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Q8WY64 (MYLIP_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Last modified July 9, 2014. Version 114. Feed History...

Clusters with 100%, 90%, 50% identity | Documents (7) | Third-party data text xml rdf/xml gff fasta
to top of pageNames·Attributes·General annotation·Ontologies·Alt products·Sequence annotation·Sequences·References·Cross-refs·Entry info·DocumentsCustomize order

Names and origin

Protein namesRecommended name:
E3 ubiquitin-protein ligase MYLIP

EC=6.3.2.-
Alternative name(s):
Inducible degrader of the LDL-receptor
Short name=Idol
Myosin regulatory light chain interacting protein
Short name=MIR
Gene names
Name:MYLIP
Synonyms:BZF1, IDOL
ORF Names:BM-023, PP5242
OrganismHomo sapiens (Human) [Reference proteome]
Taxonomic identifier9606 [NCBI]
Taxonomic lineageEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo

Protein attributes

Sequence length445 AA.
Sequence statusComplete.
Protein existenceEvidence at protein level

General annotation (Comments)

Function

E3 ubiquitin-protein ligase that mediates ubiquitination and subsequent proteasomal degradation of myosin regulatory light chain (MRLC), LDLR, VLDLR and LRP8. Activity depends on E2 enzymes of the UBE2D family. Proteasomal degradation of MRLC leads to inhibit neurite outgrowth in presence of NGF by counteracting the stabilization of MRLC by saposin-like protein (CNPY2/MSAP) and reducing CNPY2-stimulated neurite outgrowth. Acts as a sterol-dependent inhibitor of cellular cholesterol uptake by mediating ubiquitination and subsequent degradation of LDLR. Ref.1 Ref.9 Ref.10 Ref.11 Ref.12 Ref.13

Enzyme regulation

Can bind 1 iron ion per dimer. Iron binding seems to decrease LDLR degradation activity. Ref.14

Pathway

Protein modification; protein ubiquitination.

Subunit structure

Homodimer. Interacts with the E2 ubiquitin-conjugating enzyme, UBE2D1 (via RING-type zinc finger). Interacts with myosin regulatory light chain (MRLC) and TMEM4. Ref.1 Ref.10 Ref.14

Subcellular location

Cytoplasm Probable. Cell membrane; Peripheral membrane protein Ref.9.

Tissue specificity

Ubiquitously expressed. Ref.1

Developmental stage

Expressed in fetal tissues and higher levels were detected in placenta and fetal lung. Ref.1

Induction

Expression is directly activated by NR1H2 and NR1H3. Expression is not dependent of the sterol-response element-binding proteins (SREBPs). Expression is indirectly induced by LDL. Ref.11 Ref.14

Domain

The RING domain mediates ubiquitination and the neurite outgrowth inhibitory activity.

The FERM domain binds phospholipids and mediates lipoprotein receptors recognition at the plasma membrane through their cytoplasmic tails.

The RING-type zinc finger mediates the interaction with UBE2D E2 enzymes.

Post-translational modification

Autoubiquitinated.

Sequence similarities

Contains 1 FERM domain.

Contains 1 RING-type zinc finger.

Ontologies

Keywords
   Biological processUbl conjugation pathway
   Cellular componentCell membrane
Cytoplasm
Membrane
   Coding sequence diversityAlternative splicing
Polymorphism
   DomainZinc-finger
   LigandIron
Metal-binding
Zinc
   Molecular functionLigase
   PTMUbl conjugation
   Technical term3D-structure
Complete proteome
Reference proteome
Gene Ontology (GO)
   Biological_processcellular component movement

Inferred from mutant phenotype Ref.1. Source: UniProtKB

cholesterol homeostasis

Inferred from electronic annotation. Source: Ensembl

negative regulation of low-density lipoprotein particle clearance

Inferred from electronic annotation. Source: Ensembl

nervous system development

Inferred from mutant phenotype Ref.1. Source: UniProtKB

positive regulation of protein catabolic process

Inferred from electronic annotation. Source: Ensembl

protein destabilization

Inferred from electronic annotation. Source: Ensembl

protein ubiquitination

Inferred from direct assay Ref.9. Source: UniProtKB

protein ubiquitination involved in ubiquitin-dependent protein catabolic process

Inferred from electronic annotation. Source: Ensembl

regulation of low-density lipoprotein particle receptor catabolic process

Inferred from electronic annotation. Source: Ensembl

   Cellular_componentcytoplasm

Inferred from electronic annotation. Source: UniProtKB-SubCell

cytoskeleton

Inferred from electronic annotation. Source: InterPro

extrinsic component of membrane

Inferred from electronic annotation. Source: InterPro

intracellular

Inferred from direct assay Ref.1. Source: UniProtKB

plasma membrane

Inferred from electronic annotation. Source: UniProtKB-SubCell

   Molecular_functioncytoskeletal protein binding

Inferred from direct assay Ref.1. Source: UniProtKB

protein binding

Inferred from physical interaction Ref.10. Source: UniProtKB

ubiquitin-protein transferase activity

Inferred from direct assay Ref.9. Source: UniProtKB

zinc ion binding

Inferred from electronic annotation. Source: InterPro

Complete GO annotation...

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]
Isoform 1 (identifier: Q8WY64-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.
Isoform 2 (identifier: Q8WY64-2)

The sequence of this isoform differs from the canonical sequence as follows:
     1-181: Missing.
     316-445: Missing.
Note: No experimental confirmation available.

Sequence annotation (Features)

Feature keyPosition(s)LengthDescriptionGraphical viewFeature identifier

Molecule processing

Chain1 – 445445E3 ubiquitin-protein ligase MYLIP
PRO_0000055972

Regions

Domain1 – 279279FERM
Zinc finger387 – 42236RING-type
Region431 – 4333Critical for homodimerization

Sites

Metal binding3601Iron
Metal binding3631Iron
Metal binding3681Iron

Natural variations

Alternative sequence1 – 181181Missing in isoform 2.
VSP_011828
Alternative sequence316 – 445130Missing in isoform 2.
VSP_011829
Natural variant3421N → S. Ref.1 Ref.2 Ref.3 Ref.4
Corresponds to variant rs9370867 [ dbSNP | Ensembl ].
VAR_019805

Experimental info

Mutagenesis2651Y → A: Unable to clear LDLR from the plasma membrane. Ref.13
Mutagenesis2691T → R: Unable to clear LDLR from the plasma membrane. Ref.13
Mutagenesis3871C → A: Abolishes autoubiquitination. Ref.9 Ref.11 Ref.14
Mutagenesis3871C → A: Abolishes ubiquitin ligase activity. Ref.9 Ref.11 Ref.14
Mutagenesis3891V → R: Inhibits LDLR degradation. Ref.14
Mutagenesis4151L → E: Inhibits LDLR degradation. Ref.14
Sequence conflict1991K → R in AAF18974. Ref.1
Sequence conflict262 – 2632SG → TR in AAF87323. Ref.3
Sequence conflict309 – 3102KK → PRN in AAF87323. Ref.3

Secondary structure

.............. 445
Helix Strand Turn

Details...

Sequences

Sequence LengthMass (Da)Tools
Isoform 1 [UniParc].

Last modified December 20, 2005. Version 2.
Checksum: 342E643B0532B45C

FASTA44549,910
        10         20         30         40         50         60 
MLCYVTRPDA VLMEVEVEAK ANGEDCLNQV CRRLGIIEVD YFGLQFTGSK GESLWLNLRN 

        70         80         90        100        110        120 
RISQQMDGLA PYRLKLRVKF FVEPHLILQE QTRHIFFLHI KEALLAGHLL CSPEQAVELS 

       130        140        150        160        170        180 
ALLAQTKFGD YNQNTAKYNY EELCAKELSS ATLNSIVAKH KELEGTSQAS AEYQVLQIVS 

       190        200        210        220        230        240 
AMENYGIEWH SVRDSEGQKL LIGVGPEGIS ICKDDFSPIN RIAYPVVQMA TQSGKNVYLT 

       250        260        270        280        290        300 
VTKESGNSIV LLFKMISTRA ASGLYRAITE THAFYRCDTV TSAVMMQYSR DLKGHLASLF 

       310        320        330        340        350        360 
LNENINLGKK YVFDIKRTSK EVYDHARRAL YNAGVVDLVS RNNQSPSHSP LKSSESSMNC 

       370        380        390        400        410        420 
SSCEGLSCQQ TRVLQEKLRK LKEAMLCMVC CEEEINSTFC PCGHTVCCES CAAQLQSCPV 

       430        440 
CRSRVEHVQH VYLPTHTSLL NLTVI 

« Hide

Isoform 2 [UniParc].

Checksum: 377CBE27A1FAEC6E
Show »

FASTA13414,989

References

« Hide 'large scale' references
[1]"MIR is a novel ERM-like protein that interacts with myosin regulatory light chain and inhibits neurite outgrowth."
Olsson P.-A., Korhonen L., Mercer E.A., Lindholm D.
J. Biol. Chem. 274:36288-36292(1999) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), TISSUE SPECIFICITY, DEVELOPMENTAL STAGE, FUNCTION, INTERACTION WITH MYOSIN REGULATORY LIGHT CHAIN (MRLC), VARIANT SER-342.
Tissue: Brain.
[2]Shi W., Mullersman J.E.
Submitted (MAY-1997) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT SER-342.
[3]"Cloning and functional analysis of cDNAs with open reading frames for 300 previously undefined genes expressed in CD34+ hematopoietic stem/progenitor cells."
Zhang Q.-H., Ye M., Wu X.-Y., Ren S.-X., Zhao M., Zhao C.-J., Fu G., Shen Y., Fan H.-Y., Lu G., Zhong M., Xu X.-R., Han Z.-G., Zhang J.-W., Tao J., Huang Q.-H., Zhou J., Hu G.-X. expand/collapse author list , Gu J., Chen S.-J., Chen Z.
Genome Res. 10:1546-1560(2000) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2), VARIANT SER-342.
Tissue: Bone marrow.
[4]"Large-scale cDNA transfection screening for genes related to cancer development and progression."
Wan D., Gong Y., Qin W., Zhang P., Li J., Wei L., Zhou X., Li H., Qiu X., Zhong F., He L., Yu J., Yao G., Jiang H., Qian L., Yu Y., Shu H., Chen X. expand/collapse author list , Xu H., Guo M., Pan Z., Chen Y., Ge C., Yang S., Gu J.
Proc. Natl. Acad. Sci. U.S.A. 101:15724-15729(2004) [PubMed] [Europe PMC] [Abstract]
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), VARIANT SER-342.
[5]"Cloning of human full-length CDSs in BD Creator(TM) system donor vector."
Kalnine N., Chen X., Rolfs A., Halleck A., Hines L., Eisenstein S., Koundinya M., Raphael J., Moreira D., Kelley T., LaBaer J., Lin Y., Phelan M., Farmer A.
Submitted (MAY-2003) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1).
[6]"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].
[7]Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M., Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J., Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S., Turner R. expand/collapse author list , Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H., Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K., Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D., Hunkapiller M.W., Myers E.W., Venter J.C.
Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases
Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[8]"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] (ISOFORM 1).
Tissue: Placenta.
[9]"Functional activities and cellular localization of the ezrin, radixin, moesin (ERM) and RING zinc finger domains in MIR."
Bornhauser B.C., Johansson C., Lindholm D.
FEBS Lett. 553:195-199(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: MUTAGENESIS OF CYS-387, FUNCTION, SUBCELLULAR LOCATION, AUTOUBIQUITINATION.
[10]"MSAP is a novel MIR-interacting protein that enhances neurite outgrowth and increases myosin regulatory light chain."
Bornhauser B.C., Olsson P.-A., Lindholm D.
J. Biol. Chem. 278:35412-35420(2003) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INTERACTION WITH TMEM4.
[11]"LXR regulates cholesterol uptake through Idol-dependent ubiquitination of the LDL receptor."
Zelcer N., Hong C., Boyadjian R., Tontonoz P.
Science 325:100-104(2009) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, INDUCTION, MUTAGENESIS OF CYS-387.
[12]"The E3 ubiquitin ligase IDOL induces the degradation of the low density lipoprotein receptor family members VLDLR and ApoER2."
Hong C., Duit S., Jalonen P., Out R., Scheer L., Sorrentino V., Boyadjian R., Rodenburg K.W., Foley E., Korhonen L., Lindholm D., Nimpf J., van Berkel T.J., Tontonoz P., Zelcer N.
J. Biol. Chem. 285:19720-19726(2010) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION.
[13]"FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors."
Calkin A.C., Goult B.T., Zhang L., Fairall L., Hong C., Schwabe J.W., Tontonoz P.
Proc. Natl. Acad. Sci. U.S.A. 108:20107-20112(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: FUNCTION, AUTOUBIQUITINATION, MUTAGENESIS OF TYR-265 AND THR-269.
[14]"The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor."
Zhang L., Fairall L., Goult B.T., Calkin A.C., Hong C., Millard C.J., Tontonoz P., Schwabe J.W.
Genes Dev. 25:1262-1274(2011) [PubMed] [Europe PMC] [Abstract]
Cited for: X-RAY CRYSTALLOGRAPHY (2.1 ANGSTROMS) OF 369-445 IN COMPLEX WITH UBE2D1, SUBUNIT, ENZYME REGULATION, IRON-BINDING SITES, MUTAGENESIS OF CYS-387; VAL-389 AND LEU-415.
+Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ
AF187016 mRNA. Translation: AAF18974.1.
AF006003 mRNA. Translation: AAQ13408.1.
AF006004 Genomic DNA. Translation: AAQ13409.1.
AF212221 mRNA. Translation: AAF87323.1.
AF258586 mRNA. Translation: AAG23789.1.
BT007055 mRNA. Translation: AAP35704.1.
AL021407 Genomic DNA. Translation: CAI19548.1.
CH471087 Genomic DNA. Translation: EAW55366.1.
BC002860 mRNA. Translation: AAH02860.1.
CCDSCCDS4536.1. [Q8WY64-1]
RefSeqNP_037394.2. NM_013262.3. [Q8WY64-1]
UniGeneHs.484738.

3D structure databases

PDBe
RCSB-PDB
PDBj
EntryMethodResolution (Å)ChainPositionsPDBsum
2YHNX-ray3.00A/B369-445[»]
2YHOX-ray2.10A/C/E/G369-445[»]
ProteinModelPortalQ8WY64.
SMRQ8WY64. Positions 3-276, 372-441.
ModBaseSearch...
MobiDBSearch...

Protein-protein interaction databases

BioGrid118882. 13 interactions.
IntActQ8WY64. 2 interactions.
MINTMINT-268789.
STRING9606.ENSP00000349298.

Polymorphism databases

DMDM84028296.

Proteomic databases

PaxDbQ8WY64.
PRIDEQ8WY64.

Protocols and materials databases

DNASU29116.
StructuralBiologyKnowledgebaseSearch...

Genome annotation databases

EnsemblENST00000356840; ENSP00000349298; ENSG00000007944. [Q8WY64-1]
GeneID29116.
KEGGhsa:29116.
UCSCuc003nbq.3. human. [Q8WY64-1]

Organism-specific databases

CTD29116.
GeneCardsGC06P016129.
HGNCHGNC:21155. MYLIP.
MIM610082. gene.
neXtProtNX_Q8WY64.
PharmGKBPA134942677.
GenAtlasSearch...

Phylogenomic databases

eggNOGNOG149394.
HOGENOMHOG000007353.
HOVERGENHBG052549.
InParanoidQ8WY64.
KOK10637.
OMAINSTFCP.
OrthoDBEOG7060QK.
PhylomeDBQ8WY64.
TreeFamTF351936.

Enzyme and pathway databases

UniPathwayUPA00143.

Gene expression databases

ArrayExpressQ8WY64.
BgeeQ8WY64.
CleanExHS_MYLIP.
GenevestigatorQ8WY64.

Family and domain databases

Gene3D1.20.80.10. 1 hit.
2.30.29.30. 1 hit.
3.30.40.10. 1 hit.
InterProIPR019749. Band_41_domain.
IPR019750. Band_41_fam.
IPR000798. Ez/rad/moesin_like.
IPR014352. FERM/acyl-CoA-bd_prot_3-hlx.
IPR019748. FERM_central.
IPR000299. FERM_domain.
IPR018979. FERM_N.
IPR011993. PH_like_dom.
IPR029071. Ubiquitin-rel_dom.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]
PfamPF00373. FERM_M. 1 hit.
PF09379. FERM_N. 1 hit.
[Graphical view]
PRINTSPR00935. BAND41.
PR00661. ERMFAMILY.
SMARTSM00295. B41. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]
SUPFAMSSF47031. SSF47031. 1 hit.
SSF54236. SSF54236. 1 hit.
PROSITEPS50057. FERM_3. 1 hit.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]
ProtoNetSearch...

Other

GeneWikiMYLIP.
GenomeRNAi29116.
NextBio52199.
PROQ8WY64.
SOURCESearch...

Entry information

Entry nameMYLIP_HUMAN
AccessionPrimary (citable) accession number: Q8WY64
Secondary accession number(s): Q5TIA4 expand/collapse secondary AC list , Q9BU73, Q9NRL9, Q9UHE7
Entry history
Integrated into UniProtKB/Swiss-Prot: November 9, 2004
Last sequence update: December 20, 2005
Last modified: July 9, 2014
This is version 114 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

PDB cross-references

Index of Protein Data Bank (PDB) cross-references

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