Q9UKV5 (AMFR_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
E3 ubiquitin-protein ligase AMFR
EC=6.3.2.-

Alternative name(s):
Autocrine motility factor receptor
Short name=AMF receptor
RING finger protein 45
gp78

Gene names

Name:	AMFR
Synonyms:	RNF45

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	643 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	E3 ubiquitin-protein ligase that mediates the polyubiquitination of a number of proteins such as CD3D, CYP3A4, CFTR and APOB for proteasomal degradation. Component of a VCP/p97-AMFR/gp78 complex that participates in the final step of endoplasmic reticulum-associated degradation (ERAD). The VCP/p97-AMFR/gp78 complex is involved in the sterol-accelerated ERAD degradation of HMGCR through binding to the HMGCR-INSIG complex at the ER membrane and initiating ubiquitination of HMGCR. The ubiquitinated HMGCR is then released from the ER by the complex into the cytosol for subsequent destruction. Also acts as a scaffold protein to assemble a complex that couples ubiquitination, retranslocation and deglycosylation. Mediates tumor invasion and metastasis as a receptor for the GPI/autocrine motility factor. Ref.1 Ref.5 Ref.7 Ref.10
Pathway	Protein modification; protein ubiquitination.
Subunit structure	Interacts with RNF5. Also forms an ERAD complex containing VCP/p97, NGLY1; PSMC1; SAKS1 AND RAD23B required for coupling retrotranslocation, ubiquitination and deglycosylation By similarity. Interacts with DRL1. Interacts (through a region distinct from the RING finger) with UBE2G2/UBC7. Component of the VCP/p97-AMFR/gp78 complex that enhances VCP/p97 binding to polyubiquitinated proteins for their degradation by the endoplasmic reticulum-associated degradation (ERAD) pathway. Interacts (via the VIM) with VCP/p97. Interacts (via its membrane domain) with INSIG1; the interaction initiates the sterol-mediated ubiquitination and degradation of HMGCR by the ERAD pathway. Ref.5 Ref.7 Ref.8
Subcellular location	Endoplasmic reticulum membrane; Multi-pass membrane protein Ref.5.
Domain	The VCP/p97-interacting motif (VIM) is sufficient for binding VCP/p97 to form a complex capable of transfering VCP/p97 from the cytosol to microsomes.
Sequence similarities	Contains 1 CUE domain. Contains 1 RING-type zinc finger.
Sequence caution	The sequence AAA36671.1 differs from that shown. Reason: Several sequencing errors. The sequence AAA79362.1 differs from that shown. Reason: Frameshift at positions 355, 388, 411, 487, 537, 583 and 632.

Ontologies

Keywords
Biological process	Ubl conjugation pathway
Cellular component	Endoplasmic reticulum Membrane
Coding sequence diversity	Polymorphism
Domain	Transmembrane Transmembrane helix Zinc-finger
Ligand	Metal-binding Zinc
Molecular function	Ligase Receptor
PTM	Phosphoprotein
Technical term	3D-structure Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	ER-associated protein catabolic process Inferred from direct assay Ref.5. Source: UniProtKB cellular component movement Traceable author statement Ref.4. Source: ProtInc endoplasmic reticulum unfolded protein response Inferred from mutant phenotype PubMed 17157811. Source: UniProtKB protein oligomerization Inferred from direct assay PubMed 17310145. Source: UniProtKB protein polyubiquitination Inferred from direct assay PubMed 17310145Ref.10. Source: UniProtKB
Cellular_component	integral to endoplasmic reticulum membrane Inferred from direct assay Ref.5. Source: UniProtKB
Molecular_function	receptor activity Inferred from physical interaction Ref.4. Source: UniProtKB ubiquitin-protein ligase activity Inferred from direct assay Ref.5PubMed 17681147Ref.10. Source: UniProtKB zinc ion binding Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
VCP	P55072	6	EBI-1046367,EBI-355164

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 643

643

E3 ubiquitin-protein ligase AMFR

PRO_0000064579

Regions

Transmembrane

82 – 102

21

Helical; Potential

Transmembrane

122 – 142

21

Helical; Potential

Transmembrane

145 – 165

21

Helical; Potential

Transmembrane

186 – 206

21

Helical; Potential

Transmembrane

215 – 235

21

Helical; Potential

Transmembrane

276 – 296

21

Helical; Potential

Transmembrane

429 – 449

21

Helical; Potential

Domain

456 – 498

43

CUE

Zinc finger

341 – 379

39

RING-type

Region

614 – 643

30

VCP/p97-interacting motif (VIM)

Amino acid modifications

Modified residue

516

1

Phosphoserine Ref.9

Modified residue

542

1

Phosphoserine By similarity

Natural variations

Natural variant

605

1

D → V in a breast cancer sample; somatic mutation. Ref.12

VAR_035790

Experimental info

Mutagenesis

356

1

C → G: No degradation of HMGCR. Ref.7

Sequence conflict

406

1

V → D in AAA79362. Ref.3

Sequence conflict

491

1

D → V in AAA79362. Ref.3

Sequence conflict

500

1

V → L in AAA79362. Ref.3

Sequence conflict

614

1

S → L in AAD56722. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

643

Helix Strand Turn

Details...

Helix

456 – 467

12

Helix

473 – 483

11

Helix

486 – 494

9

Helix

575 – 599

25

Helix

625 – 637

13

Sequences

	Sequence		Length	Mass (Da)
	Q9UKV5 [UniParc]. Last modified June 1, 2003. Version 2. Checksum: 8782324609C0E62A	FASTA	643	72,996
	10 20 30 40 50 60 MPLLFLERFP WPSLRTYTGL SGLALLGTII SAYRALSQPE AGPGEPDQLT ASLQPEPPAP 70 80 90 100 110 120 ARPSAGGPRA RDVAQYLLSD SLFVWVLVNT ACCVLMLVAK LIQCIVFGPL RVSERQHLKD 130 140 150 160 170 180 KFWNFIFYKF IFIFGVLNVQ TVEEVVMWCL WFAGLVFLHL MVQLCKDRFE YLSFSPTTPM 190 200 210 220 230 240 SSHGRVLSLL VAMLLSCCGL AAVCSITGYT HGMHTLAFMA AESLLVTVRT AHVILRYVIH 250 260 270 280 290 300 LWDLNHEGTW EGKGTYVYYT DFVMELTLLS LDLMHHIHML LFGNIWLSMA SLVIFMQLRY 310 320 330 340 350 360 LFHEVQRRIR RHKNYLRVVG NMEARFAVAT PEELAVNNDD CAICWDSMQA ARKLPCGHLF 370 380 390 400 410 420 HNSCLRSWLE QDTSCPTCRM SLNIADNNRV REEHQGENLD ENLVPVAAAE GRPRLNQHNH 430 440 450 460 470 480 FFHFDGSRIA SWLPSFSVEV MHTTNILGIT QASNSQLNAM AHQIQEMFPQ VPYHLVLQDL 490 500 510 520 530 540 QLTRSVEITT DNILEGRIQV PFPTQRSDSI RPALNSPVER PSSDQEEGET SAQTERVPLD 550 560 570 580 590 600 LSPRLEETLD FGEVEVEPSE VEDFEARGSR FSKSADERQR MLVQRKDELL QQARKRFLNK 610 620 630 640 SSEDDAASES FLPSEGASSD PVTLRRRMLA AAAERRLQKQ QTS

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein." Shimizu K., Tani M., Watanabe H., Nagamachi Y., Niinaka Y., Shiroishi T., Ohwada S., Raz A., Yokota J. FEBS Lett. 456:295-300(1999) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION.
[2]	"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]. Tissue: Ovary.
[3]	"Identification of an upstream region that controls the transcription of the human autocrine motility factor receptor." Huang B., Xie Y., Raz A. Biochem. Biophys. Res. Commun. 212:727-742(1995) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 358-643. Tissue: Placenta.
[4]	"Purification of human tumor cell autocrine motility factor and molecular cloning of its receptor." Watanabe H., Carmi P., Hogan V., Raz T., Silletti S., Nabi I.R., Raz A. J. Biol. Chem. 266:13442-13448(1991) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 520-643.
[5]	"The tumor autocrine motility factor receptor, gp78, is a ubiquitin protein ligase implicated in degradation from the endoplasmic reticulum." Fang S., Ferrone M., Yang C., Jensen J.P., Tiwari S., Weissman A.M. Proc. Natl. Acad. Sci. U.S.A. 98:14422-14427(2001) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION AS A UBIQUITIN LIGASE, SUBCELLULAR LOCATION, INTERACTION WITH UBE2G2.
[6]	"Overexpression of the tumor autocrine motility factor receptor, gp78, a ubiquitin protein ligase (E3), results in increased ubiquitinylation and decreased secretion of apolipoprotein B100 in Hep G2 cells." Liang J.S., Kim T., Fang S., Yamaguchi J., Weissman A.M., Fisher E.A., Ginsberg H.N. J. Biol. Chem. 278:23984-23988(2003) [PubMed] [Europe PMC] [Abstract] Cited for: UBIQUITINATION OF APOB.
[7]	"Gp78, a membrane-anchored ubiquitin ligase, associates with Insig-1 and couples sterol-regulated ubiquitination to degradation of HMG CoA reductase." Song B.L., Sever N., DeBose-Boyd R.A. Mol. Cell 19:829-840(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH INSIG1 AND VCP, FUNCTION, MUTAGENESIS OF CYS-356.
[8]	"Recruitment of the p97 ATPase and ubiquitin ligases to the site of retrotranslocation at the endoplasmic reticulum membrane." Ye Y., Shibata Y., Kikkert M., van Voorden S., Wiertz E., Rapoport T.A. Proc. Natl. Acad. Sci. U.S.A. 102:14132-14138(2005) [PubMed] [Europe PMC] [Abstract] Cited for: INTERACTION WITH DERL1 AND VCP.
[9]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-516, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[10]	"CYP3A4 ubiquitination by gp78 (the tumor autocrine motility factor receptor, AMFR) and CHIP E3 ligases." Pabarcus M.K., Hoe N., Sadeghi S., Patterson C., Wiertz E., Correia M.A. Arch. Biochem. Biophys. 483:66-74(2009) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION.
[11]	"Solution structure of RSGI RUH-076, a human CUE domain." RIKEN structural genomics initiative (RSGI) Submitted (SEP-2007) to the PDB data bank Cited for: STRUCTURE BY NMR OF 452-502.
[12]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed] [Europe PMC] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] VAL-605.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBL
GenBank
DDBJ

AF124145 mRNA. Translation: AAD56722.1.
BC069197 mRNA. Translation: AAH69197.1.
L35233 mRNA. Translation: AAA79362.1. Frameshift.
M63175 mRNA. Translation: AAA36671.1. Sequence problems.

IPI

IPI00423874.
IPI00435690.

PIR

A39877.

RefSeq

NP_001135.3. NM_001144.5.

UniGene

Hs.295137.
Hs.593157.

3D structure databases

PDBe
RCSB PDB
PDBj

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
2EJS	NMR	-	A	452-502	[»]
2LVN	NMR	-	C	453-504	[»]
2LVO	NMR	-	C	453-504	[»]
2LVP	NMR	-	C	453-504	[»]
2LVQ	NMR	-	D	453-504	[»]
3FSH	X-ray	2.76	C	574-601	[»]
3H8K	X-ray	1.80	B	574-600	[»]
3TIW	X-ray	1.80	C/D	622-640	[»]
4G3O	X-ray	1.60	A	456-498	[»]

ProteinModelPortal

Q9UKV5.

ModBase

Search...

Protein-protein interaction databases

DIP

DIP-29060N.

IntAct

Q9UKV5. 13 interactions.

STRING

9606.ENSP00000290649.

PTM databases

PhosphoSite

Q9UKV5.

Polymorphism databases

DMDM

113707.
34922250.

Proteomic databases

PeptideAtlas

Q9UKV5.

PRIDE

Q9UKV5.

Protocols and materials databases

StructuralBiologyKnowledgebase

Search...

Genome annotation databases

Ensembl

ENST00000290649; ENSP00000290649; ENSG00000159461.

GeneID

267.

KEGG

hsa:267.

UCSC

uc002eiy.3. human.

Organism-specific databases

CTD

267.

GeneCards

GC16M056395.

HGNC

HGNC:463. AMFR.

HPA

CAB026381.

MIM

603243. gene.

neXtProt

NX_Q9UKV5.

PharmGKB

PA24768.

GenAtlas

Search...

Phylogenomic databases

eggNOG

COG5243.

HOGENOM

HOG000037436.

HOVERGEN

HBG044694.

InParanoid

Q9UKV5.

KO

K10636.

OMA

YTDFIME.

OrthoDB

EOG4DJJW8.

PhylomeDB

Q9UKV5.

Enzyme and pathway databases

UniPathway

UPA00143.

Gene expression databases

ArrayExpress

Q9UKV5.

Bgee

Q9UKV5.

CleanEx

HS_AMFR.

Genevestigator

Q9UKV5.

GermOnline

ENSG00000159461. Homo sapiens.

Family and domain databases

Gene3D

3.30.40.10. 1 hit.

InterPro

IPR026608. Amfr.
IPR003892. CUE.
IPR001841. Znf_RING.
IPR013083. Znf_RING/FYVE/PHD.
[Graphical view]

PANTHER

PTHR12477:SF4. PTHR12477:SF4. 1 hit.

Pfam

PF02845. CUE. 1 hit.
PF13639. zf-RING_2. 1 hit.
[Graphical view]

SMART

SM00546. CUE. 1 hit.
SM00184. RING. 1 hit.
[Graphical view]

PROSITE

PS51140. CUE. 1 hit.
PS00518. ZF_RING_1. False negative.
PS50089. ZF_RING_2. 1 hit.
[Graphical view]

ProtoNet

Search...

Other

ChiTaRS

AMFR. human.

EvolutionaryTrace

Q9UKV5.

GenomeRNAi

267.

NextBio

1049.

SOURCE

Search...

Entry information

Entry name

AMFR_HUMAN

Accession

Primary (citable) accession number: Q9UKV5
Secondary accession number(s): P26442, Q8IZ70

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 19, 2003
Last sequence update:	June 1, 2003
Last modified:	May 1, 2013
This is version 108 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.