Q8WY64 (MYLIP_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended 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

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	445 AA.
Sequence status	Complete.
Protein existence	Evidence 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 process	Ubl conjugation pathway
Cellular component	Cell membrane Cytoplasm Membrane
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Zinc-finger
Ligand	Iron Metal-binding Zinc
Molecular function	Ligase
PTM	Ubl conjugation
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	cellular component movement Inferred from mutant phenotype Ref.1. Source: UniProtKB cholesterol homeostasis Inferred from electronic annotation. Source: Compara negative regulation of low-density lipoprotein particle clearance Inferred from electronic annotation. Source: Compara nervous system development Inferred from mutant phenotype Ref.1. Source: UniProtKB positive regulation of protein catabolic process Inferred from electronic annotation. Source: Compara protein destabilization Inferred from electronic annotation. Source: Compara protein ubiquitination involved in ubiquitin-dependent protein catabolic process Inferred from electronic annotation. Source: Compara regulation of low-density lipoprotein particle receptor catabolic process Inferred from electronic annotation. Source: Compara
Cellular_component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-SubCell cytoskeleton Inferred from electronic annotation. Source: InterPro extrinsic to 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_function	cytoskeletal protein binding Inferred from direct assay Ref.1. Source: UniProtKB ubiquitin-protein ligase 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 key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 445

445

E3 ubiquitin-protein ligase MYLIP

PRO_0000055972

Regions

Domain

1 – 279

279

FERM

Zinc finger

387 – 422

36

RING-type

Region

431 – 433

3

Critical for homodimerization

Sites

Metal binding

360

1

Iron

Metal binding

363

1

Iron

Metal binding

368

1

Iron

Natural variations

Alternative sequence

1 – 181

181

Missing in isoform 2.

VSP_011828

Alternative sequence

316 – 445

130

Missing in isoform 2.

VSP_011829

Natural variant

342

1

N → S. Ref.1 Ref.2 Ref.3 Ref.4
Corresponds to variant rs9370867 [ dbSNP | Ensembl ].

VAR_019805

Experimental info

Mutagenesis

265

1

Y → A: Unable to clear LDLR from the plasma membrane. Ref.13

Mutagenesis

269

1

T → R: Unable to clear LDLR from the plasma membrane. Ref.13

Mutagenesis

387

1

C → A: Abolishes autoubiquitination. Ref.9 Ref.11 Ref.14

Mutagenesis

387

1

C → A: Abolishes ubiquitin ligase activity. Ref.9 Ref.11 Ref.14

Mutagenesis

389

1

V → R: Inhibits LDLR degradation. Ref.14

Mutagenesis

415

1

L → E: Inhibits LDLR degradation. Ref.14

Sequence conflict

199

1

K → R in AAF18974. Ref.1

Sequence conflict

262 – 263

2

SG → TR in AAF87323. Ref.3

Sequence conflict

309 – 310

2

KK → PRN in AAF87323. Ref.3

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

445

Helix Strand Turn

Details...

Helix

374 – 384

11

Turn

388 – 390

3

Beta strand

391 – 394

4

Beta strand

397 – 400

4

Helix

409 – 412

4

Turn

419 – 421

3

Beta strand

427 – 430

4

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified December 20, 2005. Version 2. Checksum: 342E643B0532B45C	FASTA	445	49,910
	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
	Isoform 2 [UniParc]. Checksum: 377CBE27A1FAEC6E	FASTA	134	14,989
	10 20 30 40 50 60 MENYGIEWHS VRDSEGQKLL IGVGPEGISI CKDDFSPINR IAYPVVQMAT QSGKNVYLTV 70 80 90 100 110 120 TKESGNSIVL LFKMISTRAA SGLYRAITET HAFYRCDTVT SAVMMQYSRD LKGHLASLFL 130 NENINLGKKY VFDI

References

	« Hide 'large scale' referencesShow '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. , 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. , 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. , 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. , 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.

IPI

IPI00242339.
IPI00642265.

RefSeq

NP_037394.2. NM_013262.3.

UniGene

Hs.484738.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2YHN	X-ray	3.00	A/B	369-445	[»]
2YHO	X-ray	2.10	A/C/E/G	369-445	[»]

ProteinModelPortal

Q8WY64.

ModBase

Search...

Protein-protein interaction databases

MINT

MINT-268789.

STRING

9606.ENSP00000349298.

Polymorphism databases

DMDM

84028296.

Proteomic databases

PaxDb

Q8WY64.

PRIDE

Q8WY64.

Protocols and materials databases

DNASU

29116.

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000356840; ENSP00000349298; ENSG00000007944.

GeneID

29116.

KEGG

hsa:29116.

UCSC

uc003nbq.3. human.

Organism-specific databases

CTD

29116.

GeneCards

GC06P016129.

HGNC

HGNC:21155. MYLIP.

MIM

610082. gene.

neXtProt

NX_Q8WY64.

PharmGKB

PA134942677.

GenAtlas

Search...

Phylogenomic databases

eggNOG

NOG149394.

HOGENOM

HOG000007353.

HOVERGEN

HBG052549.

InParanoid

Q8WY64.

KO

K10637.

OMA

INSTFCP.

OrthoDB

EOG4J1188.

PhylomeDB

Q8WY64.

Enzyme and pathway databases

UniPathway

UPA00143.

Gene expression databases

ArrayExpress

Q8WY64.

Bgee

Q8WY64.

CleanEx

HS_MYLIP.

Genevestigator

Q8WY64.

GermOnline

ENSG00000007944. Homo sapiens.

Family and domain databases

Gene3D

1.20.80.10. 1 hit.
2.30.29.30. 1 hit.
3.30.40.10. 1 hit.

InterPro

IPR019749. 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.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]

Pfam

PF00373. FERM_M. 1 hit.
PF09379. FERM_N. 1 hit.
[Graphical view]

PRINTS

PR00935. BAND41.
PR00661. ERMFAMILY.

SMART

SM00295. B41. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]

SUPFAM

SSF47031. FERM_3-hlx. 1 hit.

PROSITE

PS00660. FERM_1. False negative.
PS00661. FERM_2. False negative.
PS50057. FERM_3. 1 hit.
PS00518. ZF_RING_1. False negative.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

GenomeRNAi

29116.

NextBio

52199.

SOURCE

Search...

Entry information

Entry name

MYLIP_HUMAN

Accession

Primary (citable) accession number: Q8WY64
Secondary accession number(s): Q5TIA4 , Q9BU73, Q9NRL9, Q9UHE7

Entry history

Integrated into UniProtKB/Swiss-Prot:	November 9, 2004
Last sequence update:	December 20, 2005
Last modified:	May 1, 2013
This is version 104 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.