NEDD4

Last updated
NEDD4
NEDD4 HECT domain structure from PDB ID 2XBF.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases NEDD4 , NEDD4-1, RPF1, neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase, NEDD4 E3 ubiquitin protein ligase
External IDs OMIM: 602278 HomoloGene: 136740 GeneCards: NEDD4
Orthologs
SpeciesHumanMouse
Entrez

4734

n/a

Ensembl

ENSG00000069869

n/a

UniProt

P46934

n/a

RefSeq (mRNA)

n/a

RefSeq (protein)

n/a

Location (UCSC) Chr 15: 55.83 – 55.99 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an enzyme that is, in humans, encoded by the NEDD4 gene. [3] [4]

NEDD4 is an E3 ubiquitin ligase enzyme, that targets proteins for ubiquitination. [5] NEDD4 is, in eukaryotes, a highly conserved gene, and the founding member of the NEDD4 family of E3 HECT ubiquitin ligases, which in humans consists of 9 members: [6] [7] [8]

NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis; its eponymous protein is widely expressed, and a large number of proteins have been predicted or demonstrated to bind in vitro.

In vivo, it is involved in the regulation of a diverse range of processes, [5] including

NEDD4 also is an essential protein in animals, both for development and for survival. [9]

Structure

The NEDD4 protein has a modular structure that is shared among the NEDD4 family, consisting of an amino-terminal C2 calcium-dependent phospholipid binding domain, 3-4 WW protein-protein interaction domains, and a carboxyl-terminal catalytic HECT ubiquitin ligase domain. [10] The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates. [11] The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors. [12] The catalytic HECT domain forms a thioester bond with activated ubiquitin transferred from an E2 ubiquitin conjugating enzyme, before transferring ubiquitin directly to a specific substrate. [6]

Expression

The human NEDD4 gene is located on chromosome 15q21.3, and consists of 30 exons that transcribe five protein variants of NEDD4, all of which vary in the C2 domain but share 100% identity from the first WW domain through to the end of the protein. [13] The mouse Nedd4 gene is located on chromosome 9. [3] NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle. [14] The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery. [3] [14]

Function

In vitro, NEDD4 has been shown to bind and ubiquitinate a number of ion channels and membrane transporters resulting in their subsequent endocytosis and degradation by the proteasome, including the epithelial sodium channel (ENaC), voltage-gated calcium and voltage-gated sodium channels. [15] [16] [17] [18]

NEDD4 mediates ubiquitination and subsequent down-regulation of components of the epidermal growth factor (EGF) signalling pathway, such as HER3 and HER4 EGF receptors, and ACK. [19] [20] [21]

The fibroblast growth factor receptor 1 (FGFR1) undergoes NEDD4 mediated ubiquitination and down-regulation, and contains a novel site (VL***PSR) that binds the C2 and WW3 domain of NEDD4. [22]

There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses, [8] and NEDD4 also interacts with components of the endocytic machinery required for budding. [23]

NEDD4 can also function independently of its ubiquitin ligase activity. NEDD4 interacts with VEGFR2, leading to the degradation of VEGFR2 irrespective of whether the HECT domain is catalytically active. [24]

NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity. [16] However, in vivo studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation. [25] [26] [27]

Regulation

NEDD4 activity can be regulated by auto-inhibition, whereby the C2 domain binds to the HECT domain to create an inhibitory conformation of the protein. [28] This auto-inhibitory conformation can be disrupted by the presence of calcium, by proteins that bind to NEDD4 to prevent this conformation, or by phosphorylation of NEDD4 at specific tyrosine residues to activate NEDD4 ubiquitin ligase activity. [28] [29]

The NDFIP1 and NDFIP2 proteins function as adaptor proteins that can facilitate NEDD4 binding to substrates that lack PY motifs, as well as a role in binding NEDD4 to abrogate auto-inhibition. [30] [31] NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion. [32]

Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor. [33] Ras signalling also up-regulates NEDD4 transcription. [34]

Physiological significance

In vivo, NEDD4 is involved in the regulation of insulin and insulin-like growth factor (IGF-1) signalling by regulating the amount of insulin receptor (IR) and insulin-like growth factor 1 receptor (IGF-1R) on the cell surface. [9] [35]

The deletion of NEDD4 in mice leads to a reduced number of effector T-cells, and a slower T-cell response to antigen, suggesting that NEDD4 may function to convert naïve T-cells into activated T-cells. [36]

NEDD4 plays an important role in neuronal development, and is responsible for the formation and arborisation of dendrites in neurons by forming a signalling complex with TINK and Rap2A. [37] It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons. [38] [39]

NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking. [40] [41] The in vivo role of NEDD4 in PTEN regulation is less clear. There is some evidence from NEDD4 deficient mice that NEDD4 does not target PTEN for degradation or trafficking. [9] [42] [43] However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN. [34] [44] [45] [46] [47] NEDD4 regulation of PTEN may only occur in specific biological contexts.

The role of NEDD4 in negatively regulating tumour suppressor proteins is consistent with the frequent overexpression of NEDD4 in many different types of human cancers. [48] [49] Decreased levels of NEDD4 have also been associated with some cancers, including neuroblastoma and pancreatic cancer where the NEDD4 directly targets the respective oncoproteins N-Myc and c-Myc associated with these cancers for degradation. [50]

Viral budding

NEDD4 may be hijacked by viral proteins (for example, by UL56 from Herpes simplex virus 2, or by protein VP40 from Ebola virus. [51] Such infection aids viruses in taking over the ESCRT pathway which is essential for successful budding of the virions from the plasma membrane. [ vague ] The hijacking mechanisms operate by exploiting [ vague ] evolution, the chemical evolution of (viral) genes coding for traits that exploit a short linear motif mimicry. In the case of NEDD4, viral proteins mimic the PPxY recognition motif of WW domains that are part of NEDD4. [51]

Notes

Related Research Articles

<span class="mw-page-title-main">Ubiquitin</span> Regulatory protein found in most eukaryotic tissues

Ubiquitin is a small regulatory protein found in most tissues of eukaryotic organisms, i.e., it is found ubiquitously. It was discovered in 1975 by Gideon Goldstein and further characterized throughout the late 1970s and 1980s. Four genes in the human genome code for ubiquitin: UBB, UBC, UBA52 and RPS27A.

<span class="mw-page-title-main">Ubiquitin ligase</span> Protein

A ubiquitin ligase is a protein that recruits an E2 ubiquitin-conjugating enzyme that has been loaded with ubiquitin, recognizes a protein substrate, and assists or directly catalyzes the transfer of ubiquitin from the E2 to the protein substrate. In simple and more general terms, the ligase enables movement of ubiquitin from a ubiquitin carrier to another thing by some mechanism. The ubiquitin, once it reaches its destination, ends up being attached by an isopeptide bond to a lysine residue, which is part of the target protein. E3 ligases interact with both the target protein and the E2 enzyme, and so impart substrate specificity to the E2. Commonly, E3s polyubiquitinate their substrate with Lys48-linked chains of ubiquitin, targeting the substrate for destruction by the proteasome. However, many other types of linkages are possible and alter a protein's activity, interactions, or localization. Ubiquitination by E3 ligases regulates diverse areas such as cell trafficking, DNA repair, and signaling and is of profound importance in cell biology. E3 ligases are also key players in cell cycle control, mediating the degradation of cyclins, as well as cyclin dependent kinase inhibitor proteins. The human genome encodes over 600 putative E3 ligases, allowing for tremendous diversity in substrates.

<span class="mw-page-title-main">UBA1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-like modifier activating enzyme 1 (UBA1) is an enzyme which in humans is encoded by the UBA1 gene. UBA1 participates in ubiquitination and the NEDD8 pathway for protein folding and degradation, among many other biological processes. This protein has been linked to X-linked spinal muscular atrophy type 2, neurodegenerative diseases, and cancers.

<span class="mw-page-title-main">UBE3A</span> Protein-coding gene in Homo sapiens

Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.

<span class="mw-page-title-main">ITCH</span> Protein-coding gene in the species Homo sapiens

ITCH is a HECT domain–containing E3 ubiquitin ligase that is ablated in non-agouti-lethal 18H mice. Itchy mice develop a severe immunological phenotype after birth that includes hyperplasia of lymphoid and hematopoietic cells, and stomach and lung inflammation. In humans ITCH deficiency causes altered physical growth, craniofacial morphology defects, defective muscle development, and aberrant immune system function. The ITCH gene is located on chromosome 20 in humans. ITCH contains a C2 domain, proline-rich region, WW domains, HECT domain, and multiple amino acids that are phosphorylated and ubiquitinated.

<span class="mw-page-title-main">CBL (gene)</span> Mammalian gene

Cbl is a mammalian gene family. CBL gene, a part of the Cbl family, encodes the protein CBL which is an E3 ubiquitin-protein ligase involved in cell signalling and protein ubiquitination. Mutations to this gene have been implicated in a number of human cancers, particularly acute myeloid leukaemia.

<span class="mw-page-title-main">NEDD4L</span> Protein-coding gene in the species Homo sapiens

Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme of the NEDD4 family. In human the protein is encoded by the NEDD4L gene. In mouse the protein is commonly known as NEDD4-2 and the gene Nedd4-2.

<span class="mw-page-title-main">CBLB (gene)</span> Protein-coding gene in the species Homo sapiens

CBL-B is an E3 ubiquitin-protein ligase that in humans is encoded by the CBLB gene. CBLB is a member of the CBL gene family.

<span class="mw-page-title-main">UBE2L3</span> Protein-coding gene in humans

Ubiquitin-conjugating enzyme E2 L3 (UBE2L3), also called UBCH7, is a protein that in humans is encoded by the UBE2L3 gene. As an E2 enzyme, UBE2L3 participates in ubiquitination to target proteins for degradation. The role of UBE2L3 in the ubiquitination of the NF-κB precursor implicated it in various major autoimmune diseases, including rheumatoid arthritis (RA), celiac disease, Crohn's disease (CD), and systemic lupus erythematosus.

<span class="mw-page-title-main">SMURF1</span> Mammalian protein found in Homo sapiens

E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the SMURF1 gene. The SMURF1 Gene encodes a protein with a size of 757 amino acids and the molecular mass of this protein is 86114 Da.

<span class="mw-page-title-main">UBE2D1</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D1 is a protein that in humans is encoded by the UBE2D1 gene.

<span class="mw-page-title-main">UBE2D2</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D2 is a protein that in humans is encoded by the UBE2D2 gene.

<span class="mw-page-title-main">WWP1</span> Protein-coding gene in the species Homo sapiens

NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the WWP1 gene.

<span class="mw-page-title-main">UBE2D3</span> Protein-coding gene in the species Homo sapiens

Ubiquitin-conjugating enzyme E2 D3 is a protein that in humans is encoded by the UBE2D3 gene.

<span class="mw-page-title-main">SMURF2</span>

E3 ubiquitin-protein ligase SMURF2 is an enzyme that in humans is encoded by the SMURF2 gene which is located at chromosome 17q23.3-q24.1.

<span class="mw-page-title-main">UBE2L6</span> Protein-coding gene in the species Homo sapiens

Ubiquitin/ISG15-conjugating enzyme E2 L6 is a protein that in humans is encoded by the UBE2L6 gene.

<span class="mw-page-title-main">WWP2</span> Protein-coding gene in the species Homo sapiens

NEDD4-like E3 ubiquitin-protein ligase WWP2 also known as atrophin-1-interacting protein 2 (AIP2) or WW domain-containing protein 2 (WWP2) is an enzyme that in humans is encoded by the WWP2 gene.

The Akt signaling pathway or PI3K-Akt signaling pathway is a signal transduction pathway that promotes survival and growth in response to extracellular signals. Key proteins involved are PI3K and Akt.

<span class="mw-page-title-main">HECW1</span> Protein-coding gene in the species Homo sapiens

HECT, C2 and WW domain containing E3 ubiquitin protein ligase 1 is a protein that in humans is encoded by the HECW1 gene. In human it has 1606 amino acids and isoelectric point of 5.18.

<span class="mw-page-title-main">NDFIP1</span> Protein-coding gene in the species Homo sapiens

Nedd4 family interacting protein 1 is a protein that in humans is encoded by the NDFIP1 gene.

References

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  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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