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NEDD4L (human)

Overview NEDD4L E3 ubiquitin-protein ligase which accepts ubiquitin from an E2 ubiquitin-conjugating enzyme in the form of a thioester and then directly transfers the ubiquitin to targeted substrates. Inhibits TGF-beta signaling by triggering SMAD2 and TGFBR1 ubiquitination and proteasome-dependent degradation. Promotes ubiquitination and internalization of various plasma membrane channels such as ENaC, Nav1.2, Nav1.3, Nav1.5, Nav1.7, Nav1.8, Kv1.3, EAAT1 or CLC5. Promotes ubiquitination and degradation of SGK1 and TNK2. Interacts with UBE2E3. Interacts with NDFIP1 and NDFIP2; this interaction activates the E3 ubiquitin-protein ligase. Interacts via its WW domains with SCNN1A, SCNN1B, SCNN1G, SCN1A, SCN2A, SCN3A, SCN5A, SCN8A, SCN9A, SCN10A and CLCN5. Interacts with SMAD2, SMAD3, SMAD6 and SMAD7. The phosphorylated form interacts with 14-3-3 proteins. Interacts with Epstein-Barr virus LMP2A. Interacts with TNK2. Interacts with WNK1. Interacts with SGK1. By androgens in prostate, and by albumin in kidney. Ubiquitously expressed, with highest levels in prostate, pancreas and kidney. Activated by NDFIP1- and NDFIP2-binding. 9 isoforms of the human protein are produced by alternative splicing. Note: This description may include information from UniProtKB. Protein type: EC 6.3.2.19; Ligase; Ubiquitin conjugating system; EC 6.3.2.-; Ubiquitin ligase Cellular Component: nucleoplasm; cytoplasm; intracellular; nucleus; cytosol Molecular Function: sodium channel inhibitor activity; protein binding; sodium channel regulator activity; ubiquitin-protein ligase activity Biological Process: transcription initiation from RNA polymerase II promoter; response to metal ion; cellular sodium ion homeostasis; transcription, DNA-dependent; protein ubiquitination during ubiquitin-dependent protein catabolic process; sodium ion transport; protein ubiquitination; positive regulation of endocytosis; negative regulation of transcription from RNA polymerase II promoter; excretion; water homeostasis; regulation of membrane potential; transforming growth factor beta receptor signaling pathway; virus-host interaction; gene expression; regulation of protein catabolic process; negative regulation of transforming growth factor beta receptor signaling pathway Reference #:  Q96PU5 (UniProtKB) Alt. Names/Synonyms: E3 ubiquitin-protein ligase NEDD4-like; FLJ33870; hNedd4-2; KIAA0439; NED4L; Nedd4-2; NEDD4.2; NEDD4L; NEDL3; neural precursor cell expressed, developmentally down-regulated 4-like; neural precursor cell expressed, developmentally down-regulated gene 4-like; RSP5; ubiquitin-protein ligase NEDD4-like; ubiquitin-protein ligase Rsp5 Gene Symbols: NEDD4L Molecular weight: 111,932 Da Basal Isoelectric point: 5.56  Predict pI for various phosphorylation states Protein-Specific Antibodies or siRNAs from Cell Signaling Technology®

Select Structure to View Below NEDD4L 2LAJ - A=496-535 (human) 2LB2 - A=386-420 (human) 2LTY - B=203-217 (human) 2NSQ - A=1-154 (human) 2ONI - A=594-967 (human) 1WR3 - A=221-254 (mouse) 1WR4 - A=414-447 (mouse) 1WR7 - A=525-560 (mouse)

STRING  |  Scansite  |  Phospho.ELM  |  NetworKIN  |  Pfam  |  RCSB PDB 2LAJ 2LB2 2LTY 2NSQ 2ONI  |  ENZYME  |  Phospho3D  |  DISEASE  |  Source  |  InnateDB  |  GeneCards  |  UniProtKB  |  Entrez-Gene  |  Ensembl Gene  |  Ensembl Protein

	Sites Implicated In
inhibition: S342‑p, S428‑p molecular association, regulation: S342‑p, S448‑p phosphorylation: S342‑p, T367‑p, S448‑p

	Modification Sites and Domains	Show Modification Legend
Click here to view phosphorylation modifications only

	Modification Sites in Parent Protein, Orthologs, and Isoforms	Show Modification Legend

SS  SS: The number of records in which this modification site was determined using site-specific methods. SS methods include amino acid sequencing, site-directed mutagenesis, modification site-specific antibodies, specific MS strategies, etc.	MS  MS: The number of records in which this modification site was assigned using ONLY proteomic discovery-mode mass spectrometry.			human ► Hide Isoforms
0	1		K25	ESRILRVKVVSGIDL
0	3		Y79	PKWNEEFYFRVNPSN
0	1		K129-u	MERPYTFkDFLLRPR
0	1		S251-p	AAHRRFRsRRHISED
0	1		T302	PASPGSRTsPQELSE
0	5		S303-p	ASPGSRTsPQELSEE
0	4		T318-p	LSRRLQItPDSNGEQ
0	14		S335-p	SLIQREPssRLRsCs
0	5		S336-p	LIQREPssRLRsCsV
0	18		S340-p	EPssRLRsCsVtDAV
8	64		S342-p	ssRLRsCsVtDAVAE
0	7		T344-p	RLRsCsVtDAVAEQG
0	5		S365-p	APAGRARsstVTGGE
0	6		S366-p	PAGRARsstVTGGEE
3	16		T367-p	AGRARsstVTGGEEP
0	1		S377-p	GGEEPTPsVAyVHtT
0	2		Y380-p	EPTPsVAyVHtTPGL
0	1		T383-p	PsVAyVHtTPGLPSG
1	0		S428-p	AEDGASGsATNSNNH
0	28		S446-p	PQIRRPRsLssPTVT
9	70		S448-p	IRRPRsLssPTVTLS
0	21		S449-p	RRPRsLssPTVTLSA
0	2		T451	PRsLssPTVTLSAPL
0	1		T453	sLssPTVTLSAPLEG
0	3		K462-u	SAPLEGAkDsPVRRA
0	3		S464-p	PLEGAkDsPVRRAVk
0	2		K471-u	sPVRRAVkDtLsNPQ
0	5		T473-p	VRRAVkDtLsNPQsP
0	20		S475-p	RAVkDtLsNPQsPQP
0	67		S479-p	DtLsNPQsPQPsPyN
0	46		S483-p	NPQsPQPsPyNsPkP
0	23		Y485-p	QsPQPsPyNsPkPQH
0	58		S487-p	PQPsPyNsPkPQHKV
0	1		K489-u	PsPyNsPkPQHKVTQ
0	1		K521-u	FFIDHNTkTTTWEDP
0	1		K531-u	TWEDPRLkFPVHMRS
0	2		K539-u	FPVHMRSkTSLNPND
0	3		Y593	ITGPAVPYSREFKQK
0	2		K656-u	WIEFESEkGLDyGGV
0	3		Y660-p	ESEkGLDyGGVAREW
1	0		S795-p	VDLKPNGsEIMVTNE
0	7		Y951	NRLDLPPYETFEDLR

	NEDD4L iso5
K25	ESRILRVKVVSGIDL
Y79	PKWNEEFYFRVNPSN
K129	MERPYTFKDFLLRPR
S251	AAHRRFRSRRHISED
T302	PASPGSRTSPQELSE
S303	ASPGSRTSPQELSEE
T318	LSRRLQITPDSNGEQ
S335	SLIQREPSSRLRsCs
S336	LIQREPSSRLRsCsV
S340-p	EPSSRLRsCsVtDAV
S342-p	SSRLRsCsVtDAVAE
T344-p	RLRsCsVtDAVAEQG
-	gap
-	gap
-	gap
S357	QGHLPPPSVAYVHTT
Y360	LPPPSVAYVHTTPGL
T363	PSVAYVHTTPGLPSG
S408	AEDGASGSATNSNNH
S426	PQIRRPRSLSSPTVT
S428	IRRPRSLSSPTVTLS
S429	RRPRSLSSPTVTLSA
T431	PRSLSSPTVTLSAPL
T433	SLSSPTVTLSAPLEG
K442	SAPLEGAKDSPVRRA
S444	PLEGAKDSPVRRAVK
K451	SPVRRAVKDTLSNPQ
T453	VRRAVKDTLSNPQSP
S455	RAVKDTLSNPQSPQP
S459	DTLSNPQSPQPSPYN
S463	NPQSPQPSPYNSPKP
Y465	QSPQPSPYNSPKPQH
S467	PQPSPYNSPKPQHKV
K469	PSPYNSPKPQHKVTQ
K501	FFIDHNTKTTTWEDP
K511	TWEDPRLKFPVHMRS
K519	FPVHMRSKTSLNPND
Y573	ITGPAVPYSREFKQK
K636	WIEFESEKGLDYGGV
Y640	ESEKGLDYGGVAREW
S775	VDLKPNGSEIMVTNE
Y931	NRLDLPPYETFEDLR

	mouse ► Hide Isoforms
K53-u	ESRILRVkVVSGIDL
Y107	PKWNEEFYFRVNPSN
K157	MERPYTFKDFLLRPR
S279-p	AAHRRFRsRRHISED
T331-p	PASPVSRtsPQELSE
S332-p	ASPVSRtsPQELSEE
T347-p	VSRRLQItPDSNGEQ
S364-p	SLIQREPsSRLRsCs
S365	LIQREPsSRLRsCsV
S369-p	EPsSRLRsCsVTDTV
S371-p	sSRLRsCsVTDTVAE
T373	RLRsCsVTDTVAEQA
S394	TPTRRARSStVTGGE
S395	PTRRARSStVTGGEE
T396-p	TRRARSStVTGGEEP
S406	GGEEPTPSVAYVHTT
Y409	EPTPSVAYVHTTPGL
T412	PSVAYVHTTPGLPSG
S457	AEDGASGSATNSNNH
S475-p	PQIRRPRsLssPtVt
S477-p	IRRPRsLssPtVtLS
S478-p	RRPRsLssPtVtLSA
T480-p	PRsLssPtVtLSAPL
T482-g	sLssPtVtLSAPLEG
K491-u	SAPLEGAkDsPIRRA
S493-p	PLEGAkDsPIRRAVK
K500	sPIRRAVKDtLsNPQ
T502-p	IRRAVKDtLsNPQsP
S504-p	RAVKDtLsNPQsPQP
S508-p	DtLsNPQsPQPsPyN
S512-p	NPQsPQPsPyNsPkP
Y514-p	QsPQPsPyNsPkPQH
S516-p	PQPsPyNsPkPQHKV
K518-u	PsPyNsPkPQHKVTQ
K550	FFIDHNTKTTTWEDP
K560	TWEDPRLKFPVHMRS
K568-u	FPVHMRSkASLNPND
Y622	ITGPAVPYSREFKQK
K685-u	WIEFESEkGLDYGGV
Y689	ESEkGLDYGGVAREW
S824	VDLKPNGSEIMVTNE
Y980	NRLDLPPYETFEDLR

	NEDD4L iso3
K53	ESRILRVKVVSGIDL
Y107	PKWNEEFYFRVNPSN
K157	MERPYTFKDFLLRPR
S279	AAHRRFRSRRHISED
T331	PASPVSRTSPQELSE
S332	ASPVSRTSPQELSEE
T347	VSRRLQITPDSNGEQ
S364	SLIQREPSSRLRSCs
S365	LIQREPSSRLRSCsV
S369	EPSSRLRSCsVTDTV
S371-p	SSRLRSCsVTDTVAE
T373	RLRSCsVTDTVAEQA
-	gap
-	gap
-	gap
S386	QAHLPPPSVAYVHTT
Y389	LPPPSVAYVHTTPGL
T392	PSVAYVHTTPGLPSG
S437	AEDGASGSATNSNNH
S455	PQIRRPRSLSSPTVT
S457	IRRPRSLSSPTVTLS
S458	RRPRSLSSPTVTLSA
T460	PRSLSSPTVTLSAPL
T462	SLSSPTVTLSAPLEG
K471	SAPLEGAKDSPIRRA
S473	PLEGAKDSPIRRAVK
K480	SPIRRAVKDTLSNPQ
T482	IRRAVKDTLSNPQSP
S484	RAVKDTLSNPQSPQP
S488	DTLSNPQSPQPSPYN
S492	NPQSPQPSPYNSPKP
Y494	QSPQPSPYNSPKPQH
S496	PQPSPYNSPKPQHKV
K498	PSPYNSPKPQHKVTQ
K530	FFIDHNTKTTTWEDP
K540	TWEDPRLKFPVHMRS
K548	FPVHMRSKASLNPND
Y602	ITGPAVPYSREFKQK
K665	WIEFESEKGLDYGGV
Y669	ESEKGLDYGGVAREW
S804	VDLKPNGSEIMVTNE
Y960	NRLDLPPYETFEDLR

	rat
K12	ESRILRVKVVSGIDL
Y66-p	PKWNEEFyFRVNPSN
K116	MERPYTFKDFLLRPR
S238	AAHRRFRSRRHISED
T290	PASPVSRTSPQELSE
S291	ASPVSRTSPQELSEE
T306	LSRRLQITPDSNGEQ
S323	ALIQREPSSRLRSCS
S324	LIQREPSSRLRSCSV
S328	EPSSRLRSCSVTDTV
S330	SSRLRSCSVTDTVAE
T332	RLRSCSVTDTVAEQA
S353	TPTRRARSSTVTGGE
S354	PTRRARSSTVTGGEE
T355	TRRARSSTVTGGEES
S365	GGEESTPSVAYVHTT
Y368	ESTPSVAYVHTTPGL
T371	PSVAYVHTTPGLPSG
S416	AEDGASGSATNSNNH
S434	PQIRRPRSLssPtVT
S436-p	IRRPRSLssPtVTLS
S437-p	RRPRSLssPtVTLSA
T439-p	PRSLssPtVTLSAPL
T441	SLssPtVTLSAPLEG
K450	SAPLEGAKDSPIRRA
S452	PLEGAKDSPIRRAVK
K459	SPIRRAVKDTLSNPQ
T461	IRRAVKDTLSNPQSP
S463	RAVKDTLSNPQSPQP
S467	DTLSNPQSPQPSPyN
S471	NPQSPQPSPyNSPKP
Y473-p	QSPQPSPyNSPKPQH
S475	PQPSPyNSPKPQHKV
K477	PSPyNSPKPQHKVTQ
K509	FFIDHNTKTTTWEDP
K519	TWEDPRLKFPVHMRS
K527	FPVHMRSKASLNPND
Y581-p	ITGPAVPySREFKQK
K644	WIEFESEKGLDyGGV
Y648-p	ESEKGLDyGGVAREW
S783	VDLKPNGSEIMVTNE
Y939-p	NRLDLPPyETFEDLR

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