NEDD4

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.

{{cite journal|vauthors=Harvey KF, Kumar S | title = Nedd4-like proteins: an emerging family of ubiquitin-protein ligases implicated in diverse cellular functions | journal = Trends Cell Biol. | volume = 9 | issue = 5 | pages = 166–9 | year = 1999 | pmid = 10322449 | doi = 10.1016/s0962-8924(99)01541-x}} The C2 domain targets proteins to the phospholipid membrane, and can also be involved in targeting substrates.{{cite journal |vauthors=Dunn R, Klos DA, Adler AS, Hicke L | title = The C2 domain of the Rsp5 ubiquitin ligase binds membrane phosphoinositides and directs ubiquitination of endosomal cargo | journal = J. Cell Biol. | volume = 165 | issue = 1 | pages = 135–44 | year = 2004 | pmid = 15078904 | pmc = 2172079 | doi = 10.1083/jcb.200309026 }} The WW domains interact with proline rich PPxY motifs in target proteins to mediate interactions with substrates and adaptors.{{cite journal |vauthors=Sudol M, Chen HI, Bougeret C, Einbond A, Bork P | title = Characterization of a novel protein-binding module--the WW domain | journal = FEBS Lett. | volume = 369 | issue = 1 | pages = 67–71 | year = 1995 | pmid = 7641887 | doi = 10.1016/0014-5793(95)00550-s| s2cid = 20664267 | doi-access = }} 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.

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.{{cite web | url = https://www.ncbi.nlm.nih.gov/gene/4734 | title = NEDD4 neural precursor cell expressed, developmentally down-regulated 4, E3 ubiquitin protein ligase [Homo sapiens (human)] | publisher = NCBI }} 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.{{cite journal |vauthors=Anan T, Nagata Y, Koga H, Honda Y, Yabuki N, Miyamoto C, Kuwano A, Matsuda I, Endo F, Saya H, Nakao M | title = Human ubiquitin-protein ligase Nedd4: expression, subcellular localization and selective interaction with ubiquitin-conjugating enzymes | journal = Genes Cells | volume = 3 | issue = 11 | pages = 751–63 | year = 1998 | pmid = 9990509 | doi = 10.1046/j.1365-2443.1998.00227.x| s2cid = 1653536 }} The NEDD4 protein localizes to the cytoplasm, mainly in the perinuclear region and cytoplasmic periphery.

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.{{cite journal |vauthors=Staub O, Dho S, Henry P, Correa J, Ishikawa T, McGlade J, Rotin D | title = WW domains of Nedd4 bind to the proline-rich PY motifs in the epithelial Na+ channel deleted in Liddle's syndrome | journal = EMBO J. | volume = 15 | issue = 10 | pages = 2371–80 | year = 1996 | pmid = 8665844 | pmc = 450167 | doi = 10.1002/j.1460-2075.1996.tb00593.x}}{{cite journal |vauthors=Dinudom A, Harvey KF, Komwatana P, Young JA, Kumar S, Cook DI | title = Nedd4 mediates control of an epithelial Na+ channel in salivary duct cells by cytosolic Na+ | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 95 | issue = 12 | pages = 7169–73 | year = 1998 | pmid = 9618557 | pmc = 22776 | doi = 10.1073/pnas.95.12.7169| bibcode = 1998PNAS...95.7169D | doi-access = free }}{{cite journal |vauthors=Rougier JS, Albesa M, Abriel H, Viard P | title = Neuronal precursor cell-expressed developmentally down-regulated 4-1 (NEDD4-1) controls the sorting of newly synthesized Ca(V)1.2 calcium channels | journal = J. Biol. Chem. | volume = 286 | issue = 11 | pages = 8829–38 | year = 2011 | pmid = 21220429 | pmc = 3059038 | doi = 10.1074/jbc.M110.166520 | doi-access = free }}{{cite journal |vauthors=Fotia AB, Ekberg J, Adams DJ, Cook DI, Poronnik P, Kumar S | title = Regulation of neuronal voltage-gated sodium channels by the ubiquitin-protein ligases Nedd4 and Nedd4-2 | journal = J. Biol. Chem. | volume = 279 | issue = 28 | pages = 28930–5 | year = 2004 | pmid = 15123669 | doi = 10.1074/jbc.M402820200 | s2cid = 14519485 | url = http://espace.library.uq.edu.au/view/UQ:74618/UQ74618_OA.pdf | doi-access = free }}

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.{{cite journal |vauthors=Zeng F, Xu J, Harris RC | title = Nedd4 mediates ErbB4 JM-a/CYT-1 ICD ubiquitination and degradation in MDCK II cells | journal = FASEB J. | volume = 23 | issue = 6 | pages = 1935–45 | year = 2009 | pmid = 19193720 | pmc = 2698660 | doi = 10.1096/fj.08-121947 | doi-access = free }}{{cite journal |vauthors=Huang Z, Choi BK, Mujoo K, Fan X, Fa M, Mukherjee S, Owiti N, Zhang N, An Z | title = The E3 ubiquitin ligase NEDD4 negatively regulates HER3/ErbB3 level and signaling | journal = Oncogene | volume = 34| issue = 9| pages = 1105–15| year = 2014 | pmid = 24662824 | doi = 10.1038/onc.2014.56 | s2cid = 28296461 | doi-access = free }}{{cite journal |vauthors=Lin Q, Wang J, Childress C, Sudol M, Carey DJ, Yang W | title = HECT E3 ubiquitin ligase Nedd4-1 ubiquitinates ACK and regulates epidermal growth factor (EGF)-induced degradation of EGF receptor and ACK | journal = Mol. Cell. Biol. | volume = 30 | issue = 6 | pages = 1541–54 | year = 2010 | pmid = 20086093 | pmc = 2832494 | doi = 10.1128/MCB.00013-10 }}

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.{{cite journal |vauthors=Persaud A, Alberts P, Hayes M, Guettler S, Clarke I, Sicheri F, Dirks P, Ciruna B, Rotin D | title = Nedd4-1 binds and ubiquitylates activated FGFR1 to control its endocytosis and function | journal = EMBO J. | volume = 30 | issue = 16 | pages = 3259–73 | year = 2011 | pmid = 21765395 | pmc = 3160656 | doi = 10.1038/emboj.2011.234 }}

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.{{cite journal |vauthors=Sette P, Jadwin JA, Dussupt V, Bello NF, Bouamr F | title = The ESCRT-associated protein Alix recruits the ubiquitin ligase Nedd4-1 to facilitate HIV-1 release through the LYPXnL L domain motif | journal = J. Virol. | volume = 84 | issue = 16 | pages = 8181–92 | year = 2010 | pmid = 20519395 | pmc = 2916511 | doi = 10.1128/JVI.00634-10 }}

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.{{cite journal |vauthors=Murdaca J, Treins C, Monthouël-Kartmann MN, Pontier-Bres R, Kumar S, Van Obberghen E, Giorgetti-Peraldi S | title = Grb10 prevents Nedd4-mediated vascular endothelial growth factor receptor-2 degradation | journal = J. Biol. Chem. | volume = 279 | issue = 25 | pages = 26754–61 | year = 2004 | pmid = 15060076 | doi = 10.1074/jbc.M311802200 | doi-access = free }}

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.{{cite journal |vauthors=Kamynina E, Tauxe C, Staub O | title = Distinct characteristics of two human Nedd4 proteins with respect to epithelial Na(+) channel regulation | journal = Am. J. Physiol. Renal Physiol. | volume = 281 | issue = 3 | pages = F469–77 | year = 2001 | pmid = 11502596 | doi = 10.1152/ajprenal.2001.281.3.F469| s2cid = 3215855 }}{{cite journal |vauthors=Fotia AB, Dinudom A, Shearwin KE, Koch JP, Korbmacher C, Cook DI, Kumar S | title = The role of individual Nedd4-2 (KIAA0439) WW domains in binding and regulating epithelial sodium channels | journal = FASEB J. | volume = 17 | issue = 1 | pages = 70–2 | year = 2003 | pmid = 12424229 | doi = 10.1096/fj.02-0497fje | doi-access = free | s2cid = 10869955 }}{{cite journal |vauthors=Boase NA, Rychkov GY, Townley SL, Dinudom A, Candi E, Voss AK, Tsoutsman T, Semsarian C, Melino G, Koentgen F, Cook DI, Kumar S | title = Respiratory distress and perinatal lethality in Nedd4-2-deficient mice | journal = Nat Commun | volume = 2 | pages = 287 | year = 2011 | pmid = 21505443 | pmc = 3104547 | doi = 10.1038/ncomms1284 | bibcode = 2011NatCo...2..287B }}

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.{{cite journal |vauthors=Wang J, Peng Q, Lin Q, Childress C, Carey D, Yang W | title = Calcium activates Nedd4 E3 ubiquitin ligases by releasing the C2 domain-mediated auto-inhibition | journal = J. Biol. Chem. | volume = 285 | issue = 16 | pages = 12279–88 | year = 2010 | pmid = 20172859 | pmc = 2852967 | doi = 10.1074/jbc.M109.086405 | doi-access = free }} 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.{{cite journal |vauthors=Mund T, Pelham HR | title = Control of the activity of WW-HECT domain E3 ubiquitin ligases by NDFIP proteins | journal = EMBO Rep. | volume = 10 | issue = 5 | pages = 501–7 | year = 2009 | pmid = 19343052 | pmc = 2680872 | doi = 10.1038/embor.2009.30 }}

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.{{cite journal |vauthors=Shearwin-Whyatt L, Dalton HE, Foot N, Kumar S | title = Regulation of functional diversity within the Nedd4 family by accessory and adaptor proteins | journal = BioEssays | volume = 28 | issue = 6 | pages = 617–28 | year = 2006 | pmid = 16700065 | doi = 10.1002/bies.20422 }}{{cite journal |vauthors=Mund T, Pelham HR | title = Regulation of PTEN/Akt and MAP kinase signaling pathways by the ubiquitin ligase activators Ndfip1 and Ndfip2 | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 107 | issue = 25 | pages = 11429–34 | year = 2010 | pmid = 20534535 | pmc = 2895104 | doi = 10.1073/pnas.0911714107 | bibcode = 2010PNAS..10711429M | doi-access = free }} NDFIP1 may also regulate NEDD4 recruitment to exosomes for secretion.{{cite journal |vauthors=Howitt J, Putz U, Lackovic J, Doan A, Dorstyn L, Cheng H, Yang B, Chan-Ling T, Silke J, Kumar S, Tan SS | title = Divalent metal transporter 1 (DMT1) regulation by Ndfip1 prevents metal toxicity in human neurons | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 106 | issue = 36 | pages = 15489–94 | year = 2009 | pmid = 19706893 | pmc = 2741278 | doi = 10.1073/pnas.0904880106 | bibcode = 2009PNAS..10615489H | doi-access = free }}

Oxidative stress induces the activation of NEDD4 transcription via the FOXM1B transcription factor.{{cite journal |vauthors=Kwak YD, Wang B, Li JJ, Wang R, Deng Q, Diao S, Chen Y, Xu R, Masliah E, Xu H, Sung JJ, Liao FF | title = Upregulation of the E3 ligase NEDD4-1 by oxidative stress degrades IGF-1 receptor protein in neurodegeneration | journal = J. Neurosci. | volume = 32 | issue = 32 | pages = 10971–81 | year = 2012 | pmid = 22875931 | pmc = 3681290 | doi = 10.1523/JNEUROSCI.1836-12.2012 }} Ras signalling also up-regulates NEDD4 transcription.{{cite journal |vauthors=Zeng T, Wang Q, Fu J, Lin Q, Bi J, Ding W, Qiao Y, Zhang S, Zhao W, Lin H, Wang M, Lu B, Deng X, Zhou D, Yin Z, Wang HR | title = Impeded Nedd4-1-mediated Ras degradation underlies Ras-driven tumorigenesis | journal = Cell Rep | volume = 7 | issue = 3 | pages = 871–82 |date=May 2014 | pmid = 24746824 | doi = 10.1016/j.celrep.2014.03.045 | doi-access = free }}

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.{{cite journal |vauthors=Fan CD, Lum MA, Xu C, Black JD, Wang X | title = Ubiquitin-dependent regulation of phospho-AKT dynamics by the ubiquitin E3 ligase, NEDD4-1, in the insulin-like growth factor-1 response | journal = J. Biol. Chem. | volume = 288 | issue = 3 | pages = 1674–84 | year = 2013 | pmid = 23195959 | pmc = 3548477 | doi = 10.1074/jbc.M112.416339 | doi-access = free }}

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.{{cite journal |vauthors=Yang B, Gay DL, MacLeod MK, Cao X, Hala T, Sweezer EM, Kappler J, Marrack P, Oliver PM | title = Nedd4 augments the adaptive immune response by promoting ubiquitin-mediated degradation of Cbl-b in activated T cells | journal = Nat. Immunol. | volume = 9 | issue = 12 | pages = 1356–63 | year = 2008 | pmid = 18931680 | pmc = 2935464 | doi = 10.1038/ni.1670 }}

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.{{cite journal |vauthors=Kawabe H, Neeb A, Dimova K, Young SM, Takeda M, Katsurabayashi S, Mitkovski M, Malakhova OA, Zhang DE, Umikawa M, Kariya K, Goebbels S, Nave KA, Rosenmund C, Jahn O, Rhee J, Brose N | title = Regulation of Rap2A by the ubiquitin ligase Nedd4-1 controls neurite development | journal = Neuron | volume = 65 | issue = 3 | pages = 358–72 | year = 2010 | pmid = 20159449 | pmc = 2825371 | doi = 10.1016/j.neuron.2010.01.007 }} It is also required for proper formation and function of neuromuscular junctions, and normal numbers of cranial neural crest cells, motor neurons and axons.{{cite journal |vauthors=Liu Y, Oppenheim RW, Sugiura Y, Lin W | title = Abnormal development of the neuromuscular junction in Nedd4-deficient mice | journal = Dev. Biol. | volume = 330 | issue = 1 | pages = 153–66 | year = 2009 | pmid = 19345204 | pmc = 2810636 | doi = 10.1016/j.ydbio.2009.03.023 }}{{cite journal |vauthors=Wiszniak S, Kabbara S, Lumb R, Scherer M, Secker G, Harvey N, Kumar S, Schwarz Q | title = The ubiquitin ligase Nedd4 regulates craniofacial development by promoting cranial neural crest cell survival and stem-cell like properties | journal = Dev. Biol. | volume = 383 | issue = 2 | pages = 186–200 | year = 2013 | pmid = 24080509 | doi = 10.1016/j.ydbio.2013.09.024 | doi-access = free }}

NEDD4 has been shown to interact with and ubiquitinate the tumour suppressor protein PTEN in vitro, resulting in PTEN proteasomal degradation or trafficking.{{cite journal |vauthors=Wang X, Trotman LC, Koppie T, Alimonti A, Chen Z, Gao Z, Wang J, Erdjument-Bromage H, Tempst P, Cordon-Cardo C, Pandolfi PP, Jiang X | title = NEDD4-1 is a proto-oncogenic ubiquitin ligase for PTEN | journal = Cell | volume = 128 | issue = 1 | pages = 129–39 | year = 2007 | pmid = 17218260 | pmc = 1828909 | doi = 10.1016/j.cell.2006.11.039 }}{{cite journal |vauthors=Trotman LC, Wang X, Alimonti A, Chen Z, Teruya-Feldstein J, Yang H, Pavletich NP, Carver BS, Cordon-Cardo C, Erdjument-Bromage H, Tempst P, Chi SG, Kim HJ, Misteli T, Jiang X, Pandolfi PP | title = Ubiquitination regulates PTEN nuclear import and tumor suppression | journal = Cell | volume = 128 | issue = 1 | pages = 141–56 | year = 2007 | pmid = 17218261 | pmc = 1855245 | doi = 10.1016/j.cell.2006.11.040 }} 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.{{cite journal |vauthors=Fouladkou F, Landry T, Kawabe H, Neeb A, Lu C, Brose N, Stambolic V, Rotin D | title = The ubiquitin ligase Nedd4-1 is dispensable for the regulation of PTEN stability and localization | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 105 | issue = 25 | pages = 8585–90 | year = 2008 | pmid = 18562292 | pmc = 2438405 | doi = 10.1073/pnas.0803233105 | bibcode = 2008PNAS..105.8585F | doi-access = free }}{{cite journal |vauthors=Hsia HE, Kumar R, Luca R, Takeda M, Courchet J, Nakashima J, Wu S, Goebbels S, An W, Eickholt BJ, Polleux F, Rotin D, Wu H, Rossner MJ, Bagni C, Rhee JS, Brose N, Kawabe H | title = Ubiquitin E3 ligase Nedd4-1 acts as a downstream target of PI3K/PTEN-mTORC1 signaling to promote neurite growth | journal = Proc. Natl. Acad. Sci. U.S.A. | volume = 111 | issue = 36 | pages = 13205–10 | year = 2014 | pmid = 25157163 | doi = 10.1073/pnas.1400737111 | pmc=4246980| bibcode = 2014PNAS..11113205H | doi-access = free }} However, in other in vivo models, and in many human cancer cell lines, NEDD4 does appear responsible for the degradation of PTEN.{{cite journal |vauthors=Christie KJ, Martinez JA, Zochodne DW | title = Disruption of E3 ligase NEDD4 in peripheral neurons interrupts axon outgrowth: Linkage to PTEN | journal = Mol. Cell. Neurosci. | volume = 50 | issue = 2 | pages = 179–92 | year = 2012 | pmid = 22561198 | doi = 10.1016/j.mcn.2012.04.006 | s2cid = 21000507 }}{{cite journal |vauthors=Drinjakovic J, Jung H, Campbell DS, Strochlic L, Dwivedy A, Holt CE | title = E3 ligase Nedd4 promotes axon branching by downregulating PTEN | journal = Neuron | volume = 65 | issue = 3 | pages = 341–57 | year = 2010 | pmid = 20159448 | pmc = 2862300 | doi = 10.1016/j.neuron.2010.01.017 }}{{cite journal |vauthors=Hong SW, Moon JH, Kim JS, Shin JS, Jung KA, Lee WK, Jeong SY, Hwang JJ, Lee SJ, Suh YA, Kim I, Nam KY, Han S, Kim JE, Kim KP, Hong YS, Lee JL, Lee WJ, Choi EK, Lee JS, Jin DH, Kim TW | title = p34 is a novel regulator of the oncogenic behavior of NEDD4-1 and PTEN | journal = Cell Death Differ. | volume = 21 | issue = 1 | pages = 146–60 | year = 2014 | pmid = 24141722 | doi = 10.1038/cdd.2013.141 | pmc=3857621}}{{cite journal |vauthors=Liu J, Wan L, Liu P, Inuzuka H, Liu J, Wang Z, Wei W | title = SCF(β-TRCP)-mediated degradation of NEDD4 inhibits tumorigenesis through modulating the PTEN/Akt signaling pathway | journal = Oncotarget | volume = 5 | issue = 4 | pages = 1026–37 | year = 2014 | pmid = 24657926 | pmc = 4011580 | doi = 10.18632/oncotarget.1675}} 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.{{cite journal |vauthors=Chen C, Matesic LE | title = The Nedd4-like family of E3 ubiquitin ligases and cancer | journal = Cancer Metastasis Rev. | volume = 26 | issue = 3–4 | pages = 587–604 | year = 2007 | pmid = 17726579 | doi = 10.1007/s10555-007-9091-x | s2cid = 25942777 }}{{cite journal |vauthors=Ye X, Wang L, Shang B, Wang Z, Wei W | title = NEDD4: a promising target for cancer therapy | journal = Curr Cancer Drug Targets | volume = 14 | issue = 6 | pages = 549–56 | year = 2014 | pmid = 25088038 | doi = 10.2174/1568009614666140725092430 | pmc=4302323}} 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.{{cite journal |vauthors=Liu PY, Xu N, Malyukova A, Scarlett CJ, Sun YT, Zhang XD, Ling D, Su SP, Nelson C, Chang DK, Koach J, Tee AE, Haber M, Norris MD, Toon C, Rooman I, Xue C, Cheung BB, Kumar S, Marshall GM, Biankin AV, Liu T | title = The histone deacetylase SIRT2 stabilizes Myc oncoproteins | journal = Cell Death Differ. | volume = 20 | issue = 3 | pages = 503–14 | year = 2013 | pmid = 23175188 | pmc = 3569991 | doi = 10.1038/cdd.2012.147 }}

NEDD4 may be hijacked by viral proteins

(for example,

by UL56 from Herpes simplex virus 2, or

by protein VP40 from Ebola virus.{{cite journal | vauthors = Votteler J, Sundquist WI | title = Virus budding and the ESCRT pathway | journal = Cell Host & Microbe | volume = 14 | issue = 3 | pages = 232–41 | date = September 2013 | pmid = 24034610 | doi = 10.1016/j.chom.2013.08.012 | pmc = 3819203 | doi-access = free }}

Such infection aids viruses in taking over the ESCRT pathway which

is essential for successful budding of the virions from the plasma membrane.

{{vague|reason= opaque to anyone trying to learn de novo, rather than just jog their memory! -- BUT

• -"encyclo" means "universal" or "for all", and
• "pedia" embodies "youth", and hence "teach" |date=December 2020}}

The hijacking mechanisms operate by exploiting

{{vague|reason= do said mechanisms operate, producing exploitation, or is said molecular "mimicry" a mere analogy-based model "explaining away" of said evolution|date=December 2020}}

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.

{{Academic-written review

| wikidate = 2014

| journal = Gene

| title = {{#property:P1476|from=Q38295075}}

| Q = Q38295075

}}

{{Reflist|35em}}

• {{PDBe-KB2|P46934|E3 ubiquitin-protein ligase NEDD4}}

Category:Human proteins