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E3 ubiquitin-protein ligase NEDD4, also known as neural precursor cell expressed developmentally down-regulated protein 4 (whence "NEDD4") is an
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
that is, in humans, encoded by the ''NEDD4''
gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...
. NEDD4 is an E3 ubiquitin ligase
enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. A ...
, that targets proteins for
ubiquitination Ubiquitin is a small (8.6 kDa) 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. Fo ...
. ''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: * NEDD4 (the core topic of this article) * NEDD4-2 (or
NEDD4L Neural precursor cell expressed developmentally downregulated gene 4-like (NEDD4L) or NEDD4-2 is an enzyme (ubiquitin ligase) of the NEDD4 family. In human the protein is encoded by the ''NEDD4L'' gene. In mouse the protein is commonly known as NE ...
) *
ITCH Itch (also known as pruritus) is a sensation that causes the desire or reflex to scratch. Itch has resisted many attempts to be classified as any one type of sensory experience. Itch has many similarities to pain, and while both are unpleasant ...
*
SMURF1 E3 ubiquitin-protein ligase SMURF1 is an enzyme that in humans is encoded by the ''SMURF1'' gene. Function This gene encodes a ubiquitin ligase that is specific for receptor-regulated SMAD proteins in the bone morphogenetic protein ( BMP) pat ...
*
SMURF2 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. Interactions SMURF2 has been shown to interact with: * Mothers against decapentaplegic homolog 1, * ...
*
WWP1 NEDD4-like E3 ubiquitin-protein ligase WWP1 is an enzyme that in humans is encoded by the ''WWP1'' gene. Function WW domain-containing proteins are found in all eukaryotes and play an important role in the regulation of a wide variety of cellul ...
*
WWP2 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. Function This gene encodes a member of the ...
* NEDL1 ( HECW1) * NEDDL2 ( HECW2)]. NEDD4 regulates a large number of membrane proteins, such as ion channels and membrane receptors, via ubiquitination and endocytosis; its
eponymous An eponym is a person, a place, or a thing after whom or which someone or something is, or is believed to be, named. The adjectives which are derived from the word eponym include ''eponymous'' and ''eponymic''. Usage of the word The term ''epon ...
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, including * insulin-like growth factor signalling, * neuronal architecture, and * viral budding. NEDD4 also is an essential protein in animals, both for development and for survival.


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. The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates. The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors. 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.


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. The mouse ''Nedd4'' gene is located on chromosome 9. NEDD4 is a 120kDa protein that is expressed in most tissues, including brain, heart, lung, kidney, and skeletal muscle. The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.


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. 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. 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. There is a role for NEDD4 in viral budding via ubiquitination of viral matrix proteins for a number of viruses, and NEDD4 also interacts with components of the endocytic machinery required for budding. 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. NEDD4 can bind and ubiquitinate the epithelial sodium channel (ENaC), leading to down-regulation of sodium channel activity. However, ''in vivo'' studies have implicated the NEDD4 family member NEDD4-2 as the main ligase responsible for ENaC regulation.


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. 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. 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. NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion. Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor. Ras signalling also up-regulates NEDD4 transcription.


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. 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. 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. It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons. NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN ''in vitro'', resulting in PTEN proteasomal degradation or trafficking. 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. However, in other ''in vivo'' models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN. 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. 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.


Viral budding

NEDD4 may be
hijack Hijack may refer to: Films * ''Hijack'' (1973 film), an American made-for-television film * ''Hijack!'', a 1975 British film sponsored by the Children's Film Foundation - see Children's Film Foundation filmography * ''Hijack'' (2008 film), a Bol ...
ed by viral proteins (for example, by UL56 from
Herpes simplex virus Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), also known by their taxonomical names ''Human alphaherpesvirus 1'' and '' Human alphaherpesvirus 2'', are two members of the human ''Herpesviridae'' family, a set of viruses that produce viral inf ...
2, or by protein
VP40 In molecular biology, VP40 is the name of a viral matrix protein. Most commonly it is found in the ''Ebola virus'' (EBOV), a type of non-segmented, negative-strand RNA virus. Ebola virus causes a severe and often fatal haemorrhagic fever in h ...
from
Ebola Ebola, also known as Ebola virus disease (EVD) and Ebola hemorrhagic fever (EHF), is a viral hemorrhagic fever in humans and other primates, caused by ebolaviruses. Symptoms typically start anywhere between two days and three weeks after becom ...
virus. Such infection aids viruses in taking over the
ESCRT The endosomal sorting complexes required for transport (ESCRT) machinery is made up of cytosolic protein complexes, known as ESCRT-0, ESCRT-I, ESCRT-II, and ESCRT-III. Together with a number of accessory proteins, these ESCRT complexes enable a un ...
pathway which is essential for successful budding of the
virion A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...
s from the
plasma membrane The cell membrane (also known as the plasma membrane (PM) or cytoplasmic membrane, and historically referred to as the plasmalemma) is a biological membrane that separates and protects the interior of all cells from the outside environment (t ...
. The hijacking mechanisms operate by exploiting evolution, the chemical evolution of (viral) genes coding for traits that exploit a
short linear motif In molecular biology short linear motifs (SLiMs), linear motifs or minimotifs are short stretches of protein sequence that mediate protein–protein interaction. The first definition was given by Tim Hunt: "The sequences of many proteins contain s ...
mimicry In evolutionary biology, mimicry is an evolved resemblance between an organism and another object, often an organism of another species. Mimicry may evolve between different species, or between individuals of the same species. Often, mimicry f ...
. In the case of NEDD4, viral proteins mimic the PPxY
recognition motif Recognition may refer to: *Award, something given in recognition of an achievement Machine learning *Pattern recognition, a branch of machine learning which encompasses the meanings below Biometric * Recognition of human individuals, or biomet ...
of
WW domain The WW domain, (also known as the rsp5-domain or WWP repeating motif) is a modular protein domain that mediates specific interactions with protein ligands. This domain is found in a number of unrelated signaling and structural proteins and may be ...
s that are part of NEDD4.


Notes


References


External links

* {{PDBe-KB2, P46934, E3 ubiquitin-protein ligase NEDD4 Human proteins