Q8C863

EV
Gene name
Itch
Protein name
E3 ubiquitin-protein ligase Itchy
Names
HECT-type E3 ubiquitin transferase Itchy homolog
Species
Mus musculus (Mouse)
KEGG Pathway
mmu:16396
EC number
2.3.2.26: Aminoacyltransferases
Protein Class
HECT DOMAIN UBIQUITIN-PROTEIN LIGASE (PTHR11254)

Descriptions

E3 ubiquitin-protein ligase Itchy (Itch) is a HECT domain E3 ubiquitin ligase that provides substrate specificity to the ubiquitylation cascade and mediates the transfer of ubiquitin to substrates. In Itch, the WW domains proceeding the catalytic HECT domain play an inhibitory role by binding directly to HECT. Binding of the Ndfip1 adaptor or JNK1-mediated phosphorylation relieves the autoinhibition of Itch.

Autoinhibitory domains (AIDs)

319-472 (WW2-linker-WW3-WW4 region) EV

Target domain

509-864 (HECT domain)

Relief mechanism

PTM, Partner binding

Assay

Deletion assay, Mutagenesis experiment, Structural analysis

Accessory elements

No accessory elements

References

Autoinhibited structure

Activated structure

5 structures for Q8C863

Entry ID Method Resolution Chain Position Source
1YIU NMR - A 399-432 PDB
2JO9 NMR - A 399-432 PDB
2JOC NMR - A 399-432 PDB
5XMC X-ray 260 A A 143-864 PDB
AF-Q8C863-F1 Predicted AlphaFoldDB

24 variants for Q8C863

Variant ID(s) Position Change Description Diseaes Association Provenance
rs3388599681 202 L>R No EVA
rs3388606053 234 S>F No EVA
rs3388601587 286 Q>H No EVA
rs3388597028 290 P>S No EVA
rs3388601654 310 E>V No EVA
rs3388602726 356 R>G No EVA
rs3388596966 455 P>S No EVA
rs229336494 462 R>K No EVA
rs3388597020 528 S>N No EVA
rs3388599726 529 F>S No EVA
rs3388604010 592 N>K No EVA
rs3388605282 618 T>I No EVA
rs3388596072 621 S>P No EVA
rs3388604036 674 G>C No EVA
rs3388602746 674 G>V No EVA
rs3388599692 714 Q>H No EVA
rs3388602779 731 L>* No EVA
rs3388600697 742 L>F No EVA
rs3388606004 781 D>E No EVA
rs3388596094 789 L>V No EVA
rs3388594467 798 L>M No EVA
rs3388596095 805 D>N No EVA
rs3388602983 815 F>L No EVA
rs3388604012 817 I>M No EVA

1 associated diseases with Q8C863

Without disease ID

6 regional properties for Q8C863

Type Name Position InterPro Accession
domain C2 domain 1 - 115 IPR000008
domain HECT domain 509 - 864 IPR000569
domain WW domain 287 - 320 IPR001202-1
domain WW domain 319 - 352 IPR001202-2
domain WW domain 399 - 432 IPR001202-3
domain WW domain 439 - 472 IPR001202-4

Functions

Description
EC Number 2.3.2.26 Aminoacyltransferases
Subcellular Localization
  • Cell membrane ; Peripheral membrane protein ; Cytoplasmic side
  • Cytoplasm
  • Nucleus
  • Early endosome membrane ; Peripheral membrane protein ; Cytoplasmic side
  • Endosome membrane ; Peripheral membrane protein ; Cytoplasmic side
  • May be recruited to exosomes by NDFIP1
  • Localizes to plasma membrane upon CXCL12 stimulation where it co-localizes with CXCL4
  • Localization to early endosomes is increased upon CXCL12 stimulation where it co-localizes with DTX3L and CXCL4
PANTHER Family PTHR11254 HECT DOMAIN UBIQUITIN-PROTEIN LIGASE
PANTHER Subfamily PTHR11254:SF66 E3 UBIQUITIN-PROTEIN LIGASE ITCHY HOMOLOG
PANTHER Protein Class ubiquitin-protein ligase
PANTHER Pathway Category Ubiquitin proteasome pathway
E3

13 GO annotations of cellular component

Name Definition
cell cortex The region of a cell that lies just beneath the plasma membrane and often, but not always, contains a network of actin filaments and associated proteins.
cytoplasm The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
cytoplasmic vesicle A vesicle found in the cytoplasm of a cell.
cytosol The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
early endosome A membrane-bounded organelle that receives incoming material from primary endocytic vesicles that have been generated by clathrin-dependent and clathrin-independent endocytosis; vesicles fuse with the early endosome to deliver cargo for sorting into recycling or degradation pathways.
early endosome membrane The lipid bilayer surrounding an early endosome.
intracellular membrane-bounded organelle Organized structure of distinctive morphology and function, bounded by a single or double lipid bilayer membrane and occurring within the cell. Includes the nucleus, mitochondria, plastids, vacuoles, and vesicles. Excludes the plasma membrane.
membrane A lipid bilayer along with all the proteins and protein complexes embedded in it an attached to it.
nucleoplasm That part of the nuclear content other than the chromosomes or the nucleolus.
nucleus A membrane-bounded organelle of eukaryotic cells in which chromosomes are housed and replicated. In most cells, the nucleus contains all of the cell's chromosomes except the organellar chromosomes, and is the site of RNA synthesis and processing. In some species, or in specialized cell types, RNA metabolism or DNA replication may be absent.
plasma membrane The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
protein-containing complex A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids, carbohydrates or lipids, in which at least one component is a protein and the constituent parts function together.
ubiquitin ligase complex A protein complex that includes a ubiquitin-protein ligase and enables ubiquitin protein ligase activity. The complex also contains other proteins that may confer substrate specificity on the complex.

7 GO annotations of molecular function

Name Definition
arrestin family protein binding Binding to a member of the arrestin family, proteins involved in agonist-mediated desensitization of G protein-coupled receptors.
CXCR chemokine receptor binding Binding to a chemokine receptor in the CXCR family.
ligase activity Catalysis of the joining of two molecules, or two groups within a single molecule, using the energy from the hydrolysis of ATP, a similar triphosphate, or a pH gradient.
ribonucleoprotein complex binding Binding to a complex of RNA and protein.
ubiquitin protein ligase activity Catalysis of the transfer of ubiquitin to a substrate protein via the reaction X-ubiquitin + S -> X + S-ubiquitin, where X is either an E2 or E3 enzyme, the X-ubiquitin linkage is a thioester bond, and the S-ubiquitin linkage is an amide bond: an isopeptide bond between the C-terminal glycine of ubiquitin and the epsilon-amino group of lysine residues in the substrate or, in the linear extension of ubiquitin chains, a peptide bond the between the C-terminal glycine and N-terminal methionine of ubiquitin residues.
ubiquitin-like protein ligase binding Binding to a ubiquitin-like protein ligase, such as ubiquitin-ligase.
ubiquitin-protein transferase activity Catalysis of the transfer of ubiquitin from one protein to another via the reaction X-Ub + Y --> Y-Ub + X, where both X-Ub and Y-Ub are covalent linkages.

23 GO annotations of biological process

Name Definition
apoptotic process A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died.
CD4-positive, alpha-beta T cell proliferation The expansion of a CD4-positive, alpha-beta T cell population by cell division.
defense response to virus Reactions triggered in response to the presence of a virus that act to protect the cell or organism.
innate immune response Innate immune responses are defense responses mediated by germline encoded components that directly recognize components of potential pathogens.
negative regulation of apoptotic process Any process that stops, prevents, or reduces the frequency, rate or extent of cell death by apoptotic process.
negative regulation of CD4-positive, alpha-beta T cell proliferation Any process that stops, prevents or reduces the frequency, rate or extent of CD4-positive, alpha-beta T cell proliferation.
negative regulation of defense response to virus Any process that stops, prevents or reduces the rate or extent of antiviral mechanisms, thereby facilitating viral replication.
negative regulation of JNK cascade Any process that stops, prevents, or reduces the frequency, rate or extent of signal transduction mediated by the JNK cascade.
negative regulation of NF-kappaB transcription factor activity Any process that stops, prevents, or reduces the frequency, rate or extent of the activity of the transcription factor NF-kappaB.
positive regulation of protein catabolic process Any process that activates or increases the frequency, rate or extent of the chemical reactions and pathways resulting in the breakdown of a protein by the destruction of the native, active configuration, with or without the hydrolysis of peptide bonds.
positive regulation of receptor catabolic process Any process that activates or increases the frequency, rate or extent of receptor catabolic process.
positive regulation of T cell anergy Any process that activates or increases the frequency, rate, or extent of T cell anergy.
proteasome-mediated ubiquitin-dependent protein catabolic process The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of ubiquitin, and mediated by the proteasome.
protein autoubiquitination The ubiquitination by a protein of one or more of its own amino acid residues, or residues on an identical protein. Ubiquitination occurs on the lysine residue by formation of an isopeptide crosslink.
protein catabolic process The chemical reactions and pathways resulting in the breakdown of a protein by the destruction of the native, active configuration, with or without the hydrolysis of peptide bonds.
protein K29-linked ubiquitination A protein ubiquitination process in which a polymer of ubiquitin, formed by linkages between lysine residues at position 29 of the ubiquitin monomers, is added to a protein. K29-linked ubiquitination targets the substrate protein for degradation.
protein K48-linked ubiquitination A protein ubiquitination process in which a polymer of ubiquitin, formed by linkages between lysine residues at position 48 of the ubiquitin monomers, is added to a protein. K48-linked ubiquitination targets the substrate protein for degradation.
protein K63-linked ubiquitination A protein ubiquitination process in which a polymer of ubiquitin, formed by linkages between lysine residues at position 63 of the ubiquitin monomers, is added to a protein. K63-linked ubiquitination does not target the substrate protein for degradation, but is involved in several pathways, notably as a signal to promote error-free DNA postreplication repair.
protein polyubiquitination Addition of multiple ubiquitin groups to a protein, forming a ubiquitin chain.
protein ubiquitination The process in which one or more ubiquitin groups are added to a protein.
regulation of protein deubiquitination Any process that modulates the frequency, rate or extent of protein deubiquitination. Protein deubiquitination is the removal of one or more ubiquitin groups from a protein.
T cell anergy Any process contributing to anergy in T cells, a state of functional inactivation which is part of T cell tolerance induction.
ubiquitin-dependent protein catabolic process The chemical reactions and pathways resulting in the breakdown of a protein or peptide by hydrolysis of its peptide bonds, initiated by the covalent attachment of a ubiquitin group, or multiple ubiquitin groups, to the protein.

23 homologous proteins in AiPD

UniProt AC Gene Name Protein Name Species Evidence Code
P39940 RSP5 E3 ubiquitin-protein ligase RSP5 Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast) PR
Q9V853 Smurf E3 ubiquitin-protein ligase Smurf1 Drosophila melanogaster (Fruit fly) SS
Q9Y0H4 Su(dx) E3 ubiquitin-protein ligase Su Drosophila melanogaster (Fruit fly) SS
Q9HAU4 SMURF2 E3 ubiquitin-protein ligase SMURF2 Homo sapiens (Human) EV
O00308 WWP2 NEDD4-like E3 ubiquitin-protein ligase WWP2 Homo sapiens (Human) EV
Q9HCE7 SMURF1 E3 ubiquitin-protein ligase SMURF1 Homo sapiens (Human) PR
O95817 BAG3 BAG family molecular chaperone regulator 3 Homo sapiens (Human) PR
Q96PU5 NEDD4L E3 ubiquitin-protein ligase NEDD4-like Homo sapiens (Human) PR
O60861 GAS7 Growth arrest-specific protein 7 Homo sapiens (Human) PR
P46934 NEDD4 E3 ubiquitin-protein ligase NEDD4 Homo sapiens (Human) EV
Q9H0M0 WWP1 NEDD4-like E3 ubiquitin-protein ligase WWP1 Homo sapiens (Human) EV
Q96J02 ITCH E3 ubiquitin-protein ligase Itchy homolog Homo sapiens (Human) EV
Q60780 Gas7 Growth arrest-specific protein 7 Mus musculus (Mouse) PR
Q9CUN6 Smurf1 E3 ubiquitin-protein ligase SMURF1 Mus musculus (Mouse) PR
A2A5Z6 Smurf2 E3 ubiquitin-protein ligase SMURF2 Mus musculus (Mouse) SS
Q8BZZ3 Wwp1 NEDD4-like E3 ubiquitin-protein ligase WWP1 Mus musculus (Mouse) SS
Q9DBH0 Wwp2 NEDD4-like E3 ubiquitin-protein ligase WWP2 Mus musculus (Mouse) SS
P46935 Nedd4 E3 ubiquitin-protein ligase NEDD4 Mus musculus (Mouse) PR
Q3U0D9 Hace1 E3 ubiquitin-protein ligase HACE1 Mus musculus (Mouse) SS
Q8CFI0 Nedd4l E3 ubiquitin-protein ligase NEDD4-like Mus musculus (Mouse) PR
Q62940 Nedd4 E3 ubiquitin-protein ligase NEDD4 Rattus norvegicus (Rat) PR
Q9N2Z7 wwp-1 E3 ubiquitin-protein ligase wwp-1 Caenorhabditis elegans SS
A9JRZ0 smurf2 E3 ubiquitin-protein ligase SMURF2 Danio rerio (Zebrafish) (Brachydanio rerio) SS
10 20 30 40 50 60
MSDSGPQLDS MGSLTMKSQL QITVISAKLK ENKKNWFGPS PYVEVTVDGQ SKKTEKCNNT
70 80 90 100 110 120
NSPKWKQPLT VIVTPTSKLC FRVWSHQTLK SDVLLGTAGL DIYETLKSNN MKLEEVVMTL
130 140 150 160 170 180
QLVGDKEPTE TMGDLSVCLD GLQVEAEVVT NGETSCSEST TQNDDGCRTR DDTRVSTNGS
190 200 210 220 230 240
EDPEVAASGE NKRANGNNSP SLSNGGFKPS RPPRPSRPPP PTPRRPASVN GSPSTNSDSD
250 260 270 280 290 300
GSSTGSLPPT NTNVNTSTSE GATSGLIIPL TISGGSGPRP LNTVSQAPLP PGWEQRVDQH
310 320 330 340 350 360
GRVYYVDHVE KRTTWDRPEP LPPGWERRVD NMGRIYYVDH FTRTTTWQRP TLESVRNYEQ
370 380 390 400 410 420
WQLQRSQLQG AMQQFNQRFI YGNQDLFATS QNKEFDPLGP LPPGWEKRTD SNGRVYFVNH
430 440 450 460 470 480
NTRITQWEDP RSQGQLNEKP LPEGWEMRFT VDGIPYFVDH NRRATTYIDP RTGKSALDNG
490 500 510 520 530 540
PQIAYVRDFK AKVQYFRFWC QQLAMPQHIK ITVTRKTLFE DSFQQIMSFS PQDLRRRLWV
550 560 570 580 590 600
IFPGEEGLDY GGVAREWFFL LSHEVLNPMY CLFEYAGKDN YCLQINPASY INPDHLKYFR
610 620 630 640 650 660
FIGRFIAMAL FHGKFIDTGF SLPFYKRILN KPVGLKDLES IDPEFYNSLI WVKENNIEEC
670 680 690 700 710 720
GLEMYFSVDK EILGEIKSHD LKPNGGNILV TEENKEEYIR MVAEWRLSRG VEEQTQAFFE
730 740 750 760 770 780
GFNEILPQQY LQYFDAKELE VLLCGMQEID LNDWQRHAIY RHYTRTSKQI MWFWQFVKEI
790 800 810 820 830 840
DNEKRMRLLQ FVTGTCRLPV GGFADLMGSN GPQKFCIEKV GKENWLPRSH TCFNRLDLPP
850 860
YKSYEQLKEK LLFAIEETEG FGQE