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Protein

Adenosine monophosphate-protein transferase FICD

Gene

FICD

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Protein that can both mediate the addition of adenosine 5'-monophosphate (AMP) to specific residues of target proteins (AMPylation), and the removal of the same modification from target proteins (de-AMPylation), depending on the context (By similarity). The side chain of Glu-231 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place (By similarity). Acts as a key regulator of the ERN1/IRE1-mediated unfolded protein response (UPR) by mediating AMPylation or de-AMPylation of HSPA5/BiP (PubMed:25601083). In unstressed cells, acts as an adenylyltransferase by mediating AMPylation of HSPA5/BiP at 'Thr-518', thereby inactivating it (By similarity). In response to endoplasmic reticulum stress, acts as a phosphodiesterase by mediating removal of ATP (de-AMPylation) from HSPA5/BiP at 'Thr-518', leading to restore HSPA5/BiP activity (By similarity). Although it is able to AMPylate RhoA, Rac and Cdc42 Rho GTPases in vitro, Rho GTPases do not constitute physiological substrates (PubMed:19362538, PubMed:25601083).By similarity1 Publication3 Publications

Caution

Was initially thought to mediate AMPylation of HSPA5/BiP at 'Ser-365' and 'Thr-366' in vitro, leading to activate HSPA5/BiP (PubMed:25601083). However, it was later shown that it mediates AMPylation of HSPA5/BiP at 'Thr-518', leading to inactivate HSPA5/BiP.By similarity1 Publication

Catalytic activityi

ATP + [protein]-L-tyrosine = diphosphate + [protein]-O4-(5'-adenylyl)-L-tyrosine.1 Publication
[protein]-O4-(5'-adenylyl)-L-threonine + H2O = [protein]-L-threonine + AMP.By similarity
ATP + [protein]-L-threonine = diphosphate + [protein]-O4-(5'-adenylyl)-L-threonine.3 Publications

Cofactori

Mg2+1 Publication, Mn2+1 PublicationNote: Divalent metal cation. Prefers Mn2+ over Mg2+.1 Publication

Enzyme regulationi

The side chain of Glu-234 determines which of the two opposing activities (AMPylase or de-AMPylase) will take place. In response to endoplasmic reticulum stress, mediates de-AMPylase activity (By similarity). Adenylyltransferase activity is inhibited by the inhibitory helix present at the N-terminus: Glu-234 binds ATP and competes with ATP-binding at Arg-374, thereby preventing adenylyltransferase activity (PubMed:22266942, PubMed:25435325). In unstressed cells, disengagement of Glu-234 promotes adenylyltransferase activity (By similarity). Activation dissociates ATP-binding from Glu-234, allowing ordered binding of the entire ATP moiety with the alpha-phosphate in an orientation that is productive for accepting an incoming target hydroxyl side chain (PubMed:22266942, PubMed:25435325).By similarity2 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Binding sitei234ATP; via amide nitrogenCombined sources1 Publication1
Sitei234Important for autoinhibition of adenylyltransferase activity2 Publications1
Active sitei3631 Publication1
Binding sitei407ATPCombined sources1 Publication1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Nucleotide bindingi316 – 319ATPCombined sources1 Publication4
Nucleotide bindingi367 – 374ATPCombined sources1 Publication8
Nucleotide bindingi399 – 400ATPCombined sources1 Publication2

GO - Molecular functioni

  • ATP binding Source: UniProtKB
  • chaperone binding Source: UniProtKB
  • Hsp70 protein binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • protein adenylylhydrolase activity Source: UniProtKB
  • protein adenylyltransferase activity Source: UniProtKB
  • protein homodimerization activity Source: UniProtKB

GO - Biological processi

  • negative regulation of GTPase activity Source: UniProtKB
  • protein adenylylation Source: UniProtKB
  • protein deadenylylation Source: UniProtKB
  • regulation of IRE1-mediated unfolded protein response Source: UniProtKB
  • response to endoplasmic reticulum stress Source: UniProtKB
  • response to unfolded protein Source: UniProtKB-KW

Keywordsi

Molecular functionHydrolase, Nucleotidyltransferase, Transferase
Biological processUnfolded protein response
LigandATP-binding, Magnesium, Manganese, Nucleotide-binding

Names & Taxonomyi

Protein namesi
Recommended name:
Adenosine monophosphate-protein transferase FICDCurated (EC:2.7.7.n13 Publications)
Alternative name(s):
AMPylator FICDCurated
De-AMPylase FICDBy similarity (EC:3.1.4.-By similarity)
FIC domain-containing protein1 Publication
Huntingtin yeast partner E2 Publications
Huntingtin-interacting protein 13
Short name:
HIP-13
Huntingtin-interacting protein E2 Publications
Gene namesi
Name:FICDImported
Synonyms:HIP13, HYPE2 Publications
ORF Names:UNQ3041/PRO9857
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
Proteomesi

Organism-specific databases

EuPathDBiHostDB:ENSG00000198855.6
HGNCiHGNC:18416 FICD
neXtProtiNX_Q9BVA6

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Topology

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Topological domaini1 – 23Cytoplasmic1 PublicationAdd BLAST23
Transmembranei24 – 44Helical; Signal-anchor for type II membrane proteinSequence analysisAdd BLAST21
Topological domaini45 – 458Lumenal1 PublicationAdd BLAST414

Keywords - Cellular componenti

Endoplasmic reticulum, Membrane

Pathology & Biotechi

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi76 – 77TS → AA: Does not affect auto-AMPylation. 1 Publication2
Mutagenesisi79 – 80ST → AA: Decreased AMPylation. 1 Publication2
Mutagenesisi168T → A: Does not affect level of auto-AMPylation. 1 Publication1
Mutagenesisi170S → A: Does not affect level of auto-AMPylation. 1 Publication1
Mutagenesisi172Y → F: Does not affect level of auto-AMPylation. 1 Publication1
Mutagenesisi183T → A: Decreased AMPylation. 1 Publication1
Mutagenesisi234E → G: Promotes adenylyltransferase activity. 3 Publications1
Mutagenesisi258L → D: Abolishes homodimerization. 1 Publication1
Mutagenesisi275N → Q: Strongly decreased N-glycosylation. Abolished N-glycosylation; when associated with Q-446. 1 Publication1
Mutagenesisi363H → A: Abolishes adenylyltransferase activity. 2 Publications1
Mutagenesisi446N → Q: Slightly decreased N-glycosylation. Abolished N-glycosylation; when associated with Q-275. 1 Publication1

Organism-specific databases

OpenTargetsiENSG00000198855
PharmGKBiPA162388517

Polymorphism and mutation databases

BioMutaiFICD
DMDMi74761284

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00003173011 – 458Adenosine monophosphate-protein transferase FICDAdd BLAST458

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei79O-AMP-serine; by autocatalysis1 Publication1
Modified residuei80O-AMP-threonine; by autocatalysis1 Publication1
Modified residuei183O-AMP-threonine; by autocatalysis1 Publication1
Glycosylationi275N-linked (GlcNAc...) asparaginePROSITE-ProRule annotation1 Publication1
Glycosylationi446N-linked (GlcNAc...) asparaginePROSITE-ProRule annotation1 Publication1

Post-translational modificationi

Auto-AMPylated in vitro; it is unclear whether auto-AMPylation is relevant in vivo.2 Publications
N-glycosylated; predominantly glycosylated at Asn-275.1 Publication

Keywords - PTMi

Glycoprotein, Phosphoprotein

Proteomic databases

PaxDbiQ9BVA6
PeptideAtlasiQ9BVA6
PRIDEiQ9BVA6

PTM databases

iPTMnetiQ9BVA6
PhosphoSitePlusiQ9BVA6

Expressioni

Tissue specificityi

Ubiquitous.1 Publication

Inductioni

Up-regulated in response to activation of unfolded protein response (UPR).1 Publication

Gene expression databases

BgeeiENSG00000198855
CleanExiHS_FICD
ExpressionAtlasiQ9BVA6 baseline and differential
GenevisibleiQ9BVA6 HS

Organism-specific databases

HPAiHPA021390
HPA071134

Interactioni

Subunit structurei

Homodimer (PubMed:25435325). Interacts with HD (PubMed:9700202).2 Publications

Binary interactionsi

WithEntry#Exp.IntActNotes
itself5EBI-3907198,EBI-3907198

GO - Molecular functioni

  • chaperone binding Source: UniProtKB
  • Hsp70 protein binding Source: UniProtKB
  • identical protein binding Source: IntAct
  • protein homodimerization activity Source: UniProtKB

Protein-protein interaction databases

BioGridi116324, 3 interactors
DIPiDIP-44884N
IntActiQ9BVA6, 3 interactors
STRINGi9606.ENSP00000446479

Structurei

Secondary structure

1458
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Helixi108 – 119Combined sources12
Helixi122 – 135Combined sources14
Helixi140 – 151Combined sources12
Turni152 – 154Combined sources3
Helixi156 – 169Combined sources14
Helixi174 – 207Combined sources34
Helixi215 – 220Combined sources6
Helixi222 – 232Combined sources11
Turni233 – 235Combined sources3
Helixi240 – 249Combined sources10
Helixi258 – 277Combined sources20
Turni278 – 280Combined sources3
Helixi287 – 297Combined sources11
Turni299 – 301Combined sources3
Turni303 – 307Combined sources5
Helixi324 – 339Combined sources16
Helixi341 – 345Combined sources5
Helixi348 – 362Combined sources15
Beta strandi365 – 367Combined sources3
Helixi369 – 383Combined sources15
Helixi393 – 395Combined sources3
Helixi396 – 408Combined sources13
Helixi412 – 429Combined sources18
Helixi430 – 432Combined sources3

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
4U04X-ray2.48A/B102-445[»]
4U07X-ray2.64A/B102-445[»]
4U0SX-ray2.49A/B102-445[»]
4U0UX-ray2.98A/B102-445[»]
4U0ZX-ray2.95A/B/C/D/E/F/G/H102-445[»]
ProteinModelPortaliQ9BVA6
SMRiQ9BVA6
ModBaseiSearch...
MobiDBiSearch...

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Repeati106 – 139TPR 1Add BLAST34
Repeati140 – 173TPR 2Add BLAST34
Domaini285 – 420FidoPROSITE-ProRule annotationAdd BLAST136

Motif

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Motifi230 – 235Inhibitory (S/T)XXXE(G/N) motif1 Publication6

Domaini

The fido domain mediates the adenylyltransferase activity.1 Publication

Sequence similaritiesi

Belongs to the fic family.Curated

Keywords - Domaini

Repeat, Signal-anchor, TPR repeat, Transmembrane, Transmembrane helix

Phylogenomic databases

eggNOGiKOG3824 Eukaryota
COG3177 LUCA
GeneTreeiENSGT00390000008873
HOGENOMiHOG000008059
HOVERGENiHBG095654
InParanoidiQ9BVA6
OMAiNYAALAH
OrthoDBiEOG091G0GN7
PhylomeDBiQ9BVA6
TreeFamiTF314692

Family and domain databases

Gene3Di1.10.3290.10, 1 hit
1.25.40.10, 1 hit
InterProiView protein in InterPro
IPR003812 Fido
IPR036597 Fido-like_dom_sf
IPR013026 TPR-contain_dom
IPR011990 TPR-like_helical_dom_sf
IPR019734 TPR_repeat
PfamiView protein in Pfam
PF02661 Fic, 1 hit
SUPFAMiSSF140931 SSF140931, 1 hit
SSF48452 SSF48452, 1 hit
PROSITEiView protein in PROSITE
PS51459 FIDO, 1 hit
PS50005 TPR, 2 hits
PS50293 TPR_REGION, 1 hit

Sequencei

Sequence statusi: Complete.

Q9BVA6-1 [UniParc]FASTAAdd to basket

« Hide

        10         20         30         40         50
MMLIPMASVM AVTEPKWVSV WSRFLWVTLL SMVLGSLLAL LLPLGAVEEQ
60 70 80 90 100
CLAVLKGLYL LRSKPDRAQH AATKCTSPST ELSITSRGAT LLVAKTKASP
110 120 130 140 150
AGKLEARAAL NQALEMKRQG KREKAQKLFM HALKMDPDFV DALTEFGIFS
160 170 180 190 200
EEDKDIIQAD YLYTRALTIS PYHEKALVNR DRTLPLVEEI DQRYFSIIDS
210 220 230 240 250
KVKKVMSIPK GNSALRRVME ETYYHHIYHT VAIEGNTLTL SEIRHILETR
260 270 280 290 300
YAVPGKSLEE QNEVIGMHAA MKYINTTLVS RIGSVTISDV LEIHRRVLGY
310 320 330 340 350
VDPVEAGRFR TTQVLVGHHI PPHPQDVEKQ MQEFVQWLNS EEAMNLHPVE
360 370 380 390 400
FAALAHYKLV YIHPFIDGNG RTSRLLMNLI LMQAGYPPIT IRKEQRSDYY
410 420 430 440 450
HVLEAANEGD VRPFIRFIAK CTETTLDTLL FATTEYSVAL PEAQPNHSGF

KETLPVKP
Length:458
Mass (Da):51,778
Last modified:July 5, 2004 - v2
Checksum:i8393EAA46D61C48E
GO

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
AY358992 mRNA Translation: AAQ89351.1
CH471054 Genomic DNA Translation: EAW97813.1
BC001342 mRNA Translation: AAH01342.2
AF049611 mRNA Translation: AAC26847.1
CCDSiCCDS9116.1
RefSeqiNP_009007.2, NM_007076.2
UniGeneiHs.661891

Genome annotation databases

EnsembliENST00000552695; ENSP00000446479; ENSG00000198855
GeneIDi11153
KEGGihsa:11153
UCSCiuc001tmx.2 human

Entry informationi

Entry nameiFICD_HUMAN
AccessioniPrimary (citable) accession number: Q9BVA6
Secondary accession number(s): O75406
Entry historyiIntegrated into UniProtKB/Swiss-Prot: February 5, 2008
Last sequence update: July 5, 2004
Last modified: April 25, 2018
This is version 134 of the entry and version 2 of the sequence. See complete history.
Entry statusiReviewed (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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Reference proteome

Documents

  1. Human chromosome 12
    Human chromosome 12: entries, gene names and cross-references to MIM
  2. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  3. SIMILARITY comments
    Index of protein domains and families

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