AiPD: Autoinhibited Protein Database

Q9HAU4

Gene name	SMURF2
Protein name	E3 ubiquitin-protein ligase SMURF2
Names	hSMURF2, HECT-type E3 ubiquitin transferase SMURF2, SMAD ubiquitination regulatory factor 2, SMAD-specific E3 ubiquitin-protein ligase 2
Species	Homo sapiens (Human)
KEGG Pathway	hsa:64750
EC number	2.3.2.26: Aminoacyltransferases
Protein Class	HECT DOMAIN UBIQUITIN-PROTEIN LIGASE (PTHR11254)

Descriptions

Ubiquitination of proteins is an abundant modification that controls numerous cellular processes. The C2-WW-HECT-domain E3 Smurf2 downregulates transforming growth factor-β (TGF-β) signaling by targeting itself, the adaptor protein Smad7, and TGF-β receptor kinases for degradation. The intramolecular interaction between C2 phospholipid binding domain and HECT domain inhibits the catalytic activity of the HECT domain by obstructing accessibility of the catalytic cysteine of the HECT domain and thus blocking Smurf2-Ub thioester formation. The autoinhibition is relieved by the binding of HECT-binding domain of Smad7.

Autoinhibitory domains (AIDs)

Target domain	393-748 (HECT domain)
Relief mechanism	Partner binding
Assay	Structural analysis, Deletion assay, Mutagenesis experiment

AID

10-140 (C2 phospholipid binding domain)

Target domain

393-748 (HECT domain)

Relief mechanism

Partner binding (HECT-binding domain of Smad7 to HECT domain)

Assay

Structural analysis, Deletion assay, Mutagenesis experiment

Accessory elements

No accessory elements

References

Wiesner S et al. (2007) "Autoinhibition of the HECT-type ubiquitin ligase Smurf2 through its C2 domain", Cell, 130, 651-62

Lu K et al. (2011) "Pivotal role of the C2 domain of the Smurf1 ubiquitin ligase in substrate selection", The Journal of biological chemistry, 286, 16861-70

Ogunjimi AA et al. (2005) "Regulation of Smurf2 ubiquitin ligase activity by anchoring the E2 to the HECT domain", Molecular cell, 19, 297-308

Autoinhibited structure

Activated structure

8 structures for Q9HAU4

Entry ID	Method	Resolution	Chain	Position	Source
1ZVD	X-ray	210 A	A	369-748	PDB
2DJY	NMR	-	A	297-333	PDB
2JQZ	NMR	-	A	10-140	PDB
2KXQ	NMR	-	A	250-333	PDB
2LTZ	NMR	-	A	297-333	PDB
6FX4	X-ray	250 A	A/C	631-745	PDB
7M3Q	X-ray	250 A	A	366-748	PDB
AF-Q9HAU4-F1	Predicted				AlphaFoldDB

387 variants for Q9HAU4

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
rs1318735617 CA400794252	2	S>F		No	ClinGen gnomAD
CA293403337 rs923045599	3	N>K		No	ClinGen TOPMed gnomAD
CA400794240 rs1213043298	4	P>R		No	ClinGen TOPMed gnomAD
rs1191582356 CA400794244	4	P>T		No	ClinGen TOPMed
rs977140040 CA293403336	5	G>E		No	ClinGen TOPMed
CA293403335 rs945575581	7	R>G		No	ClinGen TOPMed
CA400794226 rs1361619880	7	R>Q		No	ClinGen gnomAD
CA400794227 rs945575581	7	R>W		No	ClinGen TOPMed
CA400794223 rs1408307619	8	R>G		No	ClinGen TOPMed
rs914060371 CA293403334	8	R>S		No	ClinGen TOPMed
CA400794215 rs1395872801	9	N>D		No	ClinGen TOPMed
CA400794213 rs1443546338	9	N>S		No	ClinGen TOPMed
CA293403333 rs866321574	10	G>E		No	ClinGen TOPMed gnomAD
CA400794185 rs1443647805	12	V>D		No	ClinGen gnomAD
rs1310385954 CA400794186	12	V>F		No	ClinGen gnomAD
CA400794165 rs1392890398	15	R>C		No	ClinGen gnomAD
CA400650713 rs1555689078	20	C>F		No	ClinGen gnomAD
CA400650685 rs1555689076	23	N>Y		No	ClinGen gnomAD
CA400650664 rs1555689075	25	V>L		No	ClinGen gnomAD
rs528493813 CA8715254	26	K>R		No	ClinGen 1000Genomes ExAC gnomAD
CA400650623 rs373389092	28	D>E		No	ClinGen ESP ExAC TOPMed gnomAD
CA400650592 rs1157249119	31	R>*		No	ClinGen TOPMed
rs1555688272 CA400649762	34	D>H		No	ClinGen gnomAD
CA400649696 rs868941342	43	G>V		No	ClinGen Ensembl
CA400649681 rs1555688260	46	Q>*		No	ClinGen gnomAD
CA8715231 rs782729221	51	D>H		No	ClinGen ExAC gnomAD
CA400649634 rs782109881	53	V>L		No	ClinGen ExAC TOPMed gnomAD
CA8715230 rs782109881	53	V>M		No	ClinGen ExAC TOPMed gnomAD
rs782449142 CA8715212	68	Y>C		No	ClinGen ExAC gnomAD
rs1415687742 CA400649505	69	I>V		No	ClinGen TOPMed gnomAD
CA8715211 rs781880349	71	K>E		No	ClinGen ExAC gnomAD
CA400649453 rs1353684331	76	T>M		No	ClinGen TOPMed gnomAD
rs781999155 CA400649444	77	I>F		No	ClinGen ExAC gnomAD
CA8715208 rs781999155	77	I>V		No	ClinGen ExAC gnomAD
rs1319285082 CA400649427	78	S>T		No	ClinGen TOPMed gnomAD
CA400649412 rs1260521768	79	V>I		No	ClinGen TOPMed
CA400649352 rs1555687858	82	H>L		No	ClinGen gnomAD
rs782489037 CA8715205	83	K>R		No	ClinGen ExAC gnomAD
CA293022207 rs777947628	90	G>D		No	ClinGen Ensembl
CA400649041 rs1251959553	95	G>D		No	ClinGen TOPMed
CA8715201 rs137900978	95	G>S		No	ClinGen ESP ExAC TOPMed gnomAD
rs139059668 CA8715200	98	R>C		No	ClinGen 1000Genomes ExAC gnomAD
rs1555687852 CA400648980	98	R>H		No	ClinGen gnomAD
CA293022196 rs139154655 COSM108829	100	L>F	skin [Cosmic]	No	ClinGen cosmic curated Ensembl
CA400648951 rs1180983372	100	L>H		No	ClinGen TOPMed gnomAD
rs1180983372 CA400648950	100	L>P		No	ClinGen TOPMed gnomAD
CA8715199 rs782631383	101	S>Y		No	ClinGen ExAC gnomAD
rs183626505 CA8715198	102	N>D		No	ClinGen 1000Genomes ExAC gnomAD
CA8715197 rs568192776	102	N>S		No	ClinGen ExAC TOPMed gnomAD
CA293022191 rs183626505	102	N>Y		No	ClinGen 1000Genomes ExAC gnomAD
CA400648892 rs1555687847	103	A>V		No	ClinGen gnomAD
CA8715196 rs80215473	105	N>S		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA293022186 rs80215473	105	N>T		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs782547508 CA8715195	106	R>C		No	ClinGen ExAC TOPMed gnomAD
CA8715194 rs781849582	106	R>H		No	ClinGen ExAC TOPMed gnomAD
CA400648842 rs781849582	106	R>L		No	ClinGen ExAC TOPMed gnomAD
rs1298824480 CA400648797	109	D>N		No	ClinGen TOPMed
CA8715172 rs373932060	112	Y>F		No	ClinGen ESP ExAC TOPMed gnomAD
rs1239853029 CA400648091	113	Q>E		No	ClinGen TOPMed
CA400648005 rs782735115	119	K>*		No	ClinGen ExAC gnomAD
rs782735115 CA8715168	119	K>Q		No	ClinGen ExAC gnomAD
CA400647974 rs1250089171	121	G>R		No	ClinGen TOPMed
rs1555687678 CA400647931	123	N>S		No	ClinGen gnomAD
rs781796522 CA8715165	124	D>N		No	ClinGen ExAC gnomAD
CA400647887 rs1178352646	125	N>S		No	ClinGen TOPMed
rs782736329 CA8715164	127	T>I		No	ClinGen ExAC gnomAD
rs1466014057 CA400647810	129	R>I		No	ClinGen TOPMed gnomAD
CA8715162 rs578188136	132	I>L		No	ClinGen ExAC TOPMed gnomAD
rs1555687676 CA400647757	132	I>T		No	ClinGen gnomAD
rs142183935 CA8715161	133	V>I		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs142183935 CA8715160	133	V>L		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA8715145 rs781875349	135	S>N		No	ClinGen ExAC gnomAD
CA400647409 rs1555687062	136	L>F		No	ClinGen gnomAD
rs1555687062 CA400647411	136	L>V		No	ClinGen gnomAD
CA400647348 rs1555687058	141	R>*		No	ClinGen gnomAD
CA8715143 rs782105740	141	R>Q		No	ClinGen ExAC gnomAD
CA8715141 rs782714771	142	I>M		No	ClinGen ExAC TOPMed gnomAD
rs145845053 CA8715142	142	I>V		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA8715140 rs782166497	143	G>D		No	ClinGen ExAC gnomAD
rs1555687049 CA400647281	147	Q>E		No	ClinGen gnomAD
CA400647277 rs1555687048	147	Q>P		No	ClinGen gnomAD
rs1555687046 CA400647230	150	D>E		No	ClinGen gnomAD
CA400647196 rs1555687045	153	R>C		No	ClinGen gnomAD
rs781984446 COSM1385320 CA8715139	153	R>H	large_intestine [Cosmic]	No	ClinGen cosmic curated ExAC TOPMed gnomAD
CA400647191 rs781984446	153	R>P		No	ClinGen ExAC TOPMed gnomAD
CA400647121 rs1555687042	158	D>N		No	ClinGen gnomAD
rs781962594 CA8715136	159	L>I		No	ClinGen ExAC TOPMed gnomAD
rs1555687041 CA400647063	162	G>S		No	ClinGen gnomAD
CA400657817 rs1598281871	163	W>G		No	ClinGen Ensembl
CA400657802 rs1598281867	165	E>K		No	ClinGen Ensembl
CA293020194 rs76552639	168	T>P		No	ClinGen Ensembl
CA8715115 rs141070223	169	A>T		No	ClinGen ESP ExAC TOPMed gnomAD
rs1555686774 CA400657742	174	Q>*		No	ClinGen Ensembl
CA400657738 rs1555686773	174	Q>H		No	ClinGen gnomAD
CA400657727 rs933502943	176	L>V		No	ClinGen TOPMed gnomAD
CA8715114 rs151084350	179	I>V		No	ClinGen ESP ExAC gnomAD
CA8715113 rs782614387	180	T>I		No	ClinGen ExAC gnomAD
rs782453858 CA8715112	182	T>A		No	ClinGen ExAC gnomAD
rs1555686766 CA400657686	182	T>S		No	ClinGen gnomAD
COSM193132 CA8715111 rs782194804	183	T>M	large_intestine [Cosmic]	No	ClinGen cosmic curated ExAC TOPMed gnomAD
rs1568183527 CA400657658	186	E>G		No	ClinGen Ensembl
CA400657660 rs1376692499	186	E>Q		No	ClinGen TOPMed
CA8715107 rs139943497	187	R>C		No	ClinGen ESP ExAC TOPMed gnomAD
CA8715106 rs186426042	189	T>A		No	ClinGen 1000Genomes ExAC gnomAD
CA293020161 rs375541957	189	T>K		No	ClinGen ESP TOPMed
rs781786195 CA400657639	190	R>*		No	ClinGen ExAC gnomAD
rs781786195 CA8715105	190	R>G		No	ClinGen ExAC gnomAD
rs1397410994 CA400657638	190	R>Q		No	ClinGen TOPMed gnomAD
CA8715088 rs782462136	191	P>L		No	ClinGen ExAC gnomAD
CA8715084 rs557992978	194	E>K		No	ClinGen 1000Genomes ExAC gnomAD
rs782738871 CA8715083	197	S>N		No	ClinGen ExAC gnomAD
rs782108294 CA8715082	197	S>R		No	ClinGen ExAC gnomAD
rs376126046 CA8715080	200	R>G		No	ClinGen ESP ExAC TOPMed gnomAD
rs782147506 CA8715079	200	R>T		No	ClinGen ExAC gnomAD
rs541086944 CA8715078	201	P>S		No	ClinGen 1000Genomes ExAC gnomAD
CA400657556 rs782380221	202	L>F		No	ClinGen ExAC gnomAD
rs782079963 CA8715076	202	L>H		No	ClinGen ExAC gnomAD
CA8715077 rs782380221	202	L>V		No	ClinGen ExAC gnomAD
CA8715075 rs781969584	204	C>R		No	ClinGen ExAC gnomAD
CA400657512 rs1555686527	208	E>G		No	ClinGen gnomAD
rs1555686524 CA400657498	210	T>A		No	ClinGen gnomAD
CA8715071 rs782409677	210	T>S		No	ClinGen ExAC gnomAD
rs782487689 CA8715068	212	I>N		No	ClinGen ExAC gnomAD
CA8715069 rs372783841	212	I>V		No	ClinGen ESP ExAC TOPMed gnomAD
rs1555686522 CA400657482	213	S>G		No	ClinGen gnomAD
rs555623415 CA8715067	214	G>E		No	ClinGen 1000Genomes ExAC gnomAD
rs1225064858 CA400657465	215	T>I		No	ClinGen TOPMed gnomAD
rs1225064858 CA400657467	215	T>K		No	ClinGen TOPMed gnomAD
CA8715066 rs782456417	216	N>K		No	ClinGen ExAC TOPMed gnomAD
CA8715064 rs535944315	218	A>T		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA400657445 rs1598280763	219	T>A		No	ClinGen Ensembl
rs782497553 CA8715061	222	Q>P		No	ClinGen ExAC TOPMed gnomAD
CA400657406 rs1182753634	225	D>H		No	ClinGen TOPMed
rs199535757 CA293019458	226	P>A		No	ClinGen 1000Genomes
CA293019457 rs370672485	226	P>L		No	ClinGen ESP TOPMed
rs1555686513 CA400657391	227	R>M		No	ClinGen gnomAD
rs1555686512 CA400657383	229	A>T		No	ClinGen gnomAD
CA400657366 rs1470645863	231	R>K		No	ClinGen TOPMed gnomAD
rs1470645863 CA400657367	231	R>T		No	ClinGen TOPMed gnomAD
rs1405934136 CA400657354	233	V>L		No	ClinGen TOPMed gnomAD
CA8715060 rs781821765	237	R>*		No	ClinGen ExAC gnomAD
CA400657327 rs1555686500	237	R>Q		No	ClinGen gnomAD
rs1555686496 CA400657321	238	H>L		No	ClinGen gnomAD
rs1555686496 CA400657320	238	H>R		No	ClinGen gnomAD
CA8715058 rs200444294	239	R>K		No	ClinGen 1000Genomes ExAC gnomAD
rs782155333 CA8715057	242	M>L		No	ClinGen ExAC TOPMed gnomAD
CA293019425 rs782155333	242	M>V		No	ClinGen ExAC TOPMed gnomAD
rs1568182444 CA400657284	243	S>N		No	ClinGen Ensembl
rs1333946595 CA400657233	250	P>L		No	ClinGen TOPMed gnomAD
rs782789235 CA8715056	250	P>S		No	ClinGen ExAC TOPMed gnomAD
CA400657237 rs782789235	250	P>T		No	ClinGen ExAC TOPMed gnomAD
CA400657232 rs782161312	251	P>A		No	ClinGen ExAC TOPMed gnomAD
CA8715055 rs782161312	251	P>S		No	ClinGen ExAC TOPMed gnomAD
CA293019386 rs537209464	254	P>S		No	ClinGen 1000Genomes
rs782388494 CA8715053	255	E>D		No	ClinGen ExAC gnomAD
CA400657208 rs1555686487	255	E>Q		No	ClinGen gnomAD
COSM215702 rs1555686484 CA400657192	257	Y>C	central_nervous_system [Cosmic]	No	ClinGen cosmic curated gnomAD
CA400657167 rs1555686270	258	E>D		No	ClinGen gnomAD
rs868918875 CA400657134	263	Q>R		No	ClinGen Ensembl
rs781963791 CA8715036	273	Q>H		No	ClinGen ExAC gnomAD
CA8715035 rs782745739	276	V>A		No	ClinGen ExAC
CA400657040 rs1555686264	277	S>R		No	ClinGen gnomAD
CA400657016 rs1555686263	280	H>R		No	ClinGen gnomAD
rs782055302 CA8715034	280	H>Y		No	ClinGen ExAC gnomAD
CA293018705 rs936523239	284	V>M		No	ClinGen Ensembl
CA8715020 rs782496140	287	D>A		No	ClinGen ExAC gnomAD
CA400656954 rs1555685609	287	D>Y		No	ClinGen gnomAD
CA8715019 rs144648010	292	N>D		No	ClinGen ESP ExAC TOPMed gnomAD
rs143629300 RCV000901308 CA8715018	292	N>S		No	ClinGen ClinVar 1000Genomes ExAC TOPMed dbSNP gnomAD
rs143629300 CA400656918	292	N>T		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA293016507 rs907955426	297	G>S		No	ClinGen Ensembl
CA8715017 rs782148640	298	P>L		No	ClinGen ExAC gnomAD
CA400656827 rs1304000901	305	I>S		No	ClinGen TOPMed gnomAD
rs782767792 CA8715015	306	R>C		No	ClinGen ExAC gnomAD
CA8715014 rs782135506	306	R>H		No	ClinGen ExAC gnomAD
CA400656820 rs1367135287	307	N>D		No	ClinGen TOPMed gnomAD
CA8715013 rs781951576	308	T>M		No	ClinGen ExAC TOPMed gnomAD
rs868917205 CA400656808	309	A>T		No	ClinGen Ensembl
CA400656785 rs1555685596	312	R>S		No	ClinGen gnomAD
CA8715009 rs782428033	316	V>I		No	ClinGen ExAC TOPMed gnomAD
rs991060957 CA293016484	317	D>E		No	ClinGen Ensembl
rs782651362 CA8715007	318	H>Q		No	ClinGen ExAC
rs1555685593 CA400656730	320	N>S		No	ClinGen gnomAD
CA8715006 rs782339787	321	R>K		No	ClinGen ExAC
CA8715004 rs782577577	328	P>L		No	ClinGen ExAC gnomAD
rs781893389 CA8715002	332	A>D		No	ClinGen ExAC gnomAD
CA8715003 rs782461463	332	A>T		No	ClinGen ExAC gnomAD
CA400656645 rs1293495242	334	L>M		No	ClinGen TOPMed
CA8714984 rs782096701	340	R>Q		No	ClinGen ExAC gnomAD
rs782244329 CA8714985	340	R>W		No	ClinGen ExAC gnomAD
CA400656574 rs1555684673	341	Q>R		No	ClinGen gnomAD
CA8714983 rs782465223	342	N>S		No	ClinGen ExAC gnomAD
CA8714980 rs782536670	346	D>E		No	ClinGen ExAC gnomAD
CA400656532 rs1391741205	347	Q>E		No	ClinGen TOPMed
rs1388804220 CA400656525	348	Q>*		No	ClinGen TOPMed
rs1598272669 CA400656503	350	Q>H		No	ClinGen Ensembl
rs781904976 CA8714979	354	S>L		No	ClinGen ExAC gnomAD
CA400656473 rs1555684671	355	L>S		No	ClinGen gnomAD
CA8714977 rs139585337	356	C>R		No	ClinGen ESP ExAC TOPMed
rs781814801 CA8714976	357	P>L		No	ClinGen ExAC gnomAD
rs781814801 CA400656458	357	P>R		No	ClinGen ExAC gnomAD
rs782753117 CA8714975	358	D>A		No	ClinGen ExAC gnomAD
CA400656449 rs1299763634	359	D>H		No	ClinGen TOPMed gnomAD
rs1339401322 CA400656441	360	T>A		No	ClinGen TOPMed gnomAD
rs1339401322 CA400656442	360	T>P		No	ClinGen TOPMed gnomAD
CA400656431 rs1598272644	361	E>V		No	ClinGen Ensembl
rs781945084 CA8714973	364	T>I		No	ClinGen ExAC gnomAD
CA8714971 rs782172449	366	P>R		No	ClinGen ExAC gnomAD
rs782799304 CA8714972	366	P>S		No	ClinGen ExAC gnomAD
CA293014381 rs992113524	367	R>T		No	ClinGen Ensembl
CA627151512 rs1555684663	368	Y>*		No	ClinGen gnomAD
rs1227039671 CA400656378 COSM3820266	370	R>G	breast [Cosmic]	No	ClinGen cosmic curated TOPMed
CA400656376 rs1555684658	370	R>L		No	ClinGen gnomAD
COSM561907 CA400656375 rs1555684658	370	R>Q	lung [Cosmic]	No	ClinGen cosmic curated gnomAD
rs1555684657 CA400656371	371	D>Y		No	ClinGen TOPMed
rs1555684655 CA400656344	375	K>Q		No	ClinGen gnomAD
CA400656317 rs1489247832	379	L>V		No	ClinGen TOPMed
rs377050276 CA400656309	380	R>L		No	ClinGen ESP ExAC gnomAD
rs377050276 CA8714967	380	R>Q		No	ClinGen ESP ExAC gnomAD
CA8714968 rs782214721	380	R>W		No	ClinGen ExAC TOPMed gnomAD
rs1189717598 CA400656306	381	Q>*		No	ClinGen TOPMed
CA400656303 rs1447662481	381	Q>H		No	ClinGen TOPMed
CA8714965 rs782271309	381	Q>R		No	ClinGen ExAC gnomAD
rs373058910 CA293014375	382	E>D		No	ClinGen ESP
rs373058910 CA400656296	382	E>D		No	ClinGen ESP
rs782683482 CA8714964	382	E>G		No	ClinGen ExAC TOPMed gnomAD
rs75814410 CA8714963	384	S>A		No	ClinGen ExAC TOPMed gnomAD
CA400656287 rs1555684648	384	S>C		No	ClinGen gnomAD
rs75814410 CA293014371	384	S>P		No	ClinGen ExAC TOPMed gnomAD
CA293014359 rs80348701	386	Q>H		No	ClinGen ExAC TOPMed gnomAD
rs782595062 CA8714961	386	Q>R		No	ClinGen ExAC
rs1292055396 CA400656271	387	Q>E		No	ClinGen TOPMed
rs926689819 CA293014354	387	Q>H		No	ClinGen Ensembl
rs267604998 CA293014345	388	P>L		No	ClinGen Ensembl
CA400656247 rs1555684644	390	A>G		No	ClinGen gnomAD
CA8714958 rs782712087	393	C>G		No	ClinGen ExAC gnomAD
CA400656227 rs1555684642	393	C>S		No	ClinGen gnomAD
rs142473670 CA8714957	394	R>C		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs782703994 CA293014314	394	R>H		No	ClinGen gnomAD
CA400656202 rs1555684640	397	V>A		No	ClinGen gnomAD
CA8714956 rs781911466	400	E>V		No	ClinGen ExAC TOPMed gnomAD
CA400656172 rs1362955329 COSM982956	401	E>D	endometrium [Cosmic]	No	ClinGen cosmic curated TOPMed
rs782498467 CA8714935	405	E>G		No	ClinGen ExAC TOPMed gnomAD
CA8714934 COSM108626 rs150764181	408	R>*	skin [Cosmic]	No	ClinGen cosmic curated ExAC gnomAD
rs527467892 CA8714933	408	R>Q		No	ClinGen 1000Genomes ExAC gnomAD
CA400656106 rs1555684525	409	Q>H		No	ClinGen gnomAD
rs782492471 CA8714932	410	V>F		No	ClinGen ExAC TOPMed gnomAD
rs782784564 CA8714930	411	M>I		No	ClinGen ExAC gnomAD
CA400656095 rs1555684524	411	M>T		No	ClinGen gnomAD
rs782157707 CA400656020	421	R>*		No	ClinGen ExAC TOPMed gnomAD
CA8714928 rs781853124	421	R>Q		No	ClinGen ExAC gnomAD
CA400656007 rs1555684516	423	M>K		No	ClinGen gnomAD
CA400656009 rs1555684517	423	M>V		No	ClinGen gnomAD
CA8714927 rs782791805	424	I>T		No	ClinGen ExAC TOPMed gnomAD
rs568303941 CA8714926	427	R>C		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA8714925 rs548461235	427	R>H		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs548461235 CA8714924	427	R>L		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA400655977 rs548461235	427	R>P		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs1448162080 CA400655930	434	Y>C		No	ClinGen TOPMed
rs1241084746 CA400655912	437	V>F		No	ClinGen TOPMed gnomAD
rs1241084746 CA400655914	437	V>I		No	ClinGen TOPMed gnomAD
rs868979789 CA400655867	441	W>C		No	ClinGen Ensembl
rs1555684153 CA400655861	442	L>F		No	ClinGen gnomAD
CA400655864 rs1555684154	442	L>V		No	ClinGen gnomAD
rs1027046103 CA293013384	442	L>W		No	ClinGen Ensembl
rs782201745 CA8714896	443	Y>C		No	ClinGen ExAC gnomAD
CA8714895 rs782033893	446	S>T		No	ClinGen ExAC gnomAD
rs1555684149 CA400655781	453	Y>*		No	ClinGen gnomAD
CA293013370 rs536626033	454	Y>H		No	ClinGen 1000Genomes
rs1345700345 CA400655751	458	Q>*		No	ClinGen TOPMed
CA8714893 rs782258625	462	D>Y		No	ClinGen ExAC gnomAD
rs1555684140 CA400655705	464	I>T		No	ClinGen gnomAD
rs782168725 CA8714890	469	I>S		No	ClinGen ExAC gnomAD
rs372100026 CA293013346	469	I>V		No	ClinGen ESP
rs1452847143 CA400655668	470	N>H		No	ClinGen TOPMed
CA8714888 rs782530682	470	N>S		No	ClinGen ExAC TOPMed gnomAD
rs1555684135 CA400655653	472	D>Y		No	ClinGen gnomAD
rs1003030091 CA293013339	476	N>K		No	ClinGen Ensembl
rs534931526 CA8714885	477	P>L		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs534931526 CA400655618	477	P>R		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
CA8714866 rs782508163	478	E>*		No	ClinGen ExAC gnomAD
rs1218893944 CA400655589	480	L>V		No	ClinGen TOPMed
rs1555684008 CA400655578	481	S>F		No	ClinGen gnomAD
rs1273385074 CA400655573	482	Y>C		No	ClinGen TOPMed
rs1202846325 CA400655532	488	R>*		No	ClinGen TOPMed gnomAD
CA8714863 rs782611657	488	R>Q		No	ClinGen ExAC gnomAD
CA400655521 rs1568172507	490	M>V		No	ClinGen Ensembl
rs782497053 CA8714862	494	V>M		No	ClinGen ExAC gnomAD
rs75189975 CA293012888	497	G>*		No	ClinGen Ensembl
CA400655466 rs1250971827	498	H>N		No	ClinGen TOPMed gnomAD
rs924811026 CA293012886	503	G>S		No	ClinGen Ensembl
rs782082677 CA8714856	514	G>E		No	ClinGen ExAC gnomAD
CA400655344 rs1555684002	515	K>T		No	ClinGen gnomAD
CA400655339 rs1555684000	516	S>A		No	ClinGen gnomAD
CA8714854 rs782691276	517	I>V		No	ClinGen ExAC TOPMed gnomAD
rs782059614 CA8714853	519	L>F		No	ClinGen ExAC gnomAD
CA400655290 rs1167162278	523	E>K		No	ClinGen TOPMed
rs1555683990 CA400655280	524	L>S		No	ClinGen gnomAD
rs1370419958 CA400655274	525	V>L		No	ClinGen TOPMed
COSM108066 rs142348673 CA293012847	529	L>F	skin [Cosmic]	No	ClinGen cosmic curated Ensembl
rs782115668 CA8714850	531	N>S		No	ClinGen ExAC TOPMed gnomAD
CA400655218 rs1329438595	533	L>V		No	ClinGen TOPMed gnomAD
rs1555683984 CA400655208	534	V>A		No	ClinGen gnomAD
rs1568172425 CA400655191	536	I>M		No	ClinGen Ensembl
rs912073687 CA293012666	538	E>A		No	ClinGen Ensembl
CA8714836 rs782154487	541	I>T		No	ClinGen ExAC TOPMed gnomAD
CA8714835 rs781850491	543	G>S		No	ClinGen ExAC gnomAD
rs1300208435 CA400655122	545	L>S		No	ClinGen TOPMed
rs373923799 CA293012652	547	H>Y		No	ClinGen ESP TOPMed gnomAD
rs1214388552 CA400655102	548	T>A		No	ClinGen TOPMed
rs370520140 CA8714832	548	T>I		No	ClinGen ESP ExAC TOPMed gnomAD
rs370520140 CA8714833	548	T>N		No	ClinGen ESP ExAC TOPMed gnomAD
rs1555683914 CA400655083	551	V>I		No	ClinGen gnomAD
rs781942844 CA8714831	554	N>I		No	ClinGen ExAC
rs1555683907 CA400655039	557	G>S		No	ClinGen gnomAD
CA400655001 rs1555683906	562	H>Y		No	ClinGen gnomAD
CA8714830 rs782311363	567	N>T		No	ClinGen ExAC gnomAD
CA400654951 rs782068855	569	K>R		No	ClinGen ExAC gnomAD
rs782068855 CA8714829	569	K>T		No	ClinGen ExAC gnomAD
CA8714828 rs376057787	572	P>T		No	ClinGen ESP ExAC gnomAD
rs1324087352 CA400654909	575	E>G		No	ClinGen TOPMed gnomAD
CA400654893 rs1555683902	577	N>S		No	ClinGen gnomAD
CA8714826 rs782254986	581	Y>C		No	ClinGen ExAC gnomAD
rs1555683636 CA400654822	585	Y>C		No	ClinGen gnomAD
CA400654825 rs1462110985	585	Y>H		No	ClinGen TOPMed
CA400654814 rs1555683630	586	V>A		No	ClinGen gnomAD
CA400654816 rs1555683632	586	V>L		No	ClinGen gnomAD
CA293011616 rs946839927	592	R>Q		No	ClinGen TOPMed gnomAD
rs1555683629 CA400654759	594	I>T		No	ClinGen gnomAD
rs370936838 CA8714811	600	A>T		No	ClinGen ESP ExAC TOPMed gnomAD
rs1555683615 CA400654656	609	I>V		No	ClinGen gnomAD
rs1299897510 CA400654625	613	L>Q		No	ClinGen TOPMed
CA8714810 rs528473359	616	T>A		No	ClinGen 1000Genomes ExAC gnomAD
rs781908426 CA8714794	626	I>V		No	ClinGen ExAC gnomAD
rs369022089 CA8714793	632	I>R		No	ClinGen ESP ExAC TOPMed gnomAD
rs781834617 CA8714791	639	V>L		No	ClinGen ExAC gnomAD
CA8714789 rs782062513	642	R>Q		No	ClinGen ExAC TOPMed gnomAD
rs201657151 CA8714790	642	R>W		No	ClinGen ExAC TOPMed gnomAD
CA293008500 rs200599554	646	C>R		No	ClinGen 1000Genomes
rs143406890 CA293008499	647	T>A		No	ClinGen 1000Genomes ESP TOPMed gnomAD
CA400654374 rs1284690481	648	P>A		No	ClinGen TOPMed
CA8714787 rs782806262	652	I>T		No	ClinGen ExAC gnomAD
CA293008495 rs886219870	652	I>V		No	ClinGen Ensembl
rs1206676998 CA400654338	653	V>F		No	ClinGen TOPMed
CA400654267 rs1555683271	662	F>C		No	ClinGen gnomAD
rs1555683268 CA400654230	667	R>Q		No	ClinGen gnomAD
rs1555683262 CA400654227	668	R>*		No	ClinGen gnomAD
rs1555683260 CA400654225	668	R>Q		No	ClinGen gnomAD
rs1555683259 CA400654199	672	L>H		No	ClinGen gnomAD
CA400654152 rs1555683258	679	S>C		No	ClinGen gnomAD
rs1555683255 CA400654149	680	R>*		No	ClinGen gnomAD
CA400654148 rs1555683254	680	R>Q		No	ClinGen gnomAD
CA400654143 rs1472251357	681	V>L		No	ClinGen TOPMed
rs113252908 CA293008484	682	P>S		No	ClinGen Ensembl
CA400654130 rs1555683252	683	L>R		No	ClinGen gnomAD
rs1555683253 CA400654133	683	L>V		No	ClinGen gnomAD
CA8714782 rs781927037	686	F>L		No	ClinGen ExAC gnomAD
CA400654095 rs1158850450	688	A>V		No	ClinGen TOPMed
CA400654088 rs1555683250	689	L>F		No	ClinGen gnomAD
CA400654059 rs1555683111	691	G>D		No	ClinGen gnomAD
rs782355511 CA8714758	692	A>T		No	ClinGen ExAC gnomAD
CA400654046 rs1555683109	694	G>S		No	ClinGen gnomAD
rs967823528 CA293008002	695	P>L		No	ClinGen TOPMed gnomAD
rs369610090 CA8714755	699	T>S		No	ClinGen ESP ExAC TOPMed gnomAD
CA400654008 rs1189270387	700	I>V		No	ClinGen TOPMed
CA400653995 rs1568168474	701	H>Q		No	ClinGen Ensembl
CA8714753 rs550472832	703	I>M		No	ClinGen ExAC TOPMed gnomAD
rs782399154 CA8714754	703	I>T		No	ClinGen ExAC gnomAD
COSM3820263 CA400653981 rs1555683103	704	D>N	breast [Cosmic]	No	ClinGen cosmic curated gnomAD
CA8714752 rs782639687	705	A>D		No	ClinGen ExAC gnomAD
CA8714751 rs782509803	708	N>D		No	ClinGen ExAC gnomAD
CA400653912 rs1555683101	714	H>Y		No	ClinGen gnomAD
CA8714737 rs559722942	718	N>S		No	ClinGen 1000Genomes ExAC gnomAD
CA400653854 rs1410795652	720	I>M		No	ClinGen TOPMed
CA8714735 rs782368903	724	P>L		No	ClinGen ExAC gnomAD
rs782027289 CA8714736	724	P>S		No	ClinGen ExAC gnomAD
rs1555683066 CA400653824	725	Y>C		No	ClinGen gnomAD
CA400653809 rs1555683063	727	S>N		No	ClinGen gnomAD
CA400653806 rs868963448	727	S>R		No	ClinGen Ensembl
rs1555683061 CA400653800	728	Y>C		No	ClinGen gnomAD
rs782591760 CA8714733	729	E>Q		No	ClinGen ExAC gnomAD
CA400653776 rs1555683059	732	Y>H		No	ClinGen gnomAD
CA400653738 rs1598264530	737	T>I		No	ClinGen Ensembl
CA293007795 rs79487944	737	T>P		No	ClinGen Ensembl
CA400653701 rs1555683054	743	C>R		No	ClinGen gnomAD
CA400653690 rs1371800885	744	G>A		No	ClinGen TOPMed
CA8714729 rs141646442	747	V>M		No	ClinGen ExAC TOPMed gnomAD

No associated diseases with Q9HAU4

5 regional properties for Q9HAU4

Type	Name	Position	InterPro Accession
domain	C2 domain	1 - 119	IPR000008
domain	HECT domain	393 - 748	IPR000569
domain	WW domain	157 - 190	IPR001202-1
domain	WW domain	251 - 284	IPR001202-2
domain	WW domain	297 - 330	IPR001202-3

Functions

		Description
EC Number	2.3.2.26	Aminoacyltransferases
Subcellular Localization	Nucleus Cytoplasm Cell membrane Membrane raft	Cytoplasmic in the presence of SMAD7 Colocalizes with CAV1, SMAD7 and TGF-beta receptor in membrane rafts
PANTHER Family	PTHR11254	HECT DOMAIN UBIQUITIN-PROTEIN LIGASE
PANTHER Subfamily	PTHR11254:SF300	E3 UBIQUITIN-PROTEIN LIGASE SMURF2
PANTHER Protein Class	ubiquitin-protein ligase
PANTHER Pathway Category	Ubiquitin proteasome pathway E3 TGF-beta signaling pathway Smurfs

8 GO annotations of cellular component

Name	Definition
cytoplasm	The contents of a cell excluding the plasma membrane and nucleus, but including other subcellular structures.
cytosol	The part of the cytoplasm that does not contain organelles but which does contain other particulate matter, such as protein complexes.
membrane raft	Any of the small (10-200 nm), heterogeneous, highly dynamic, sterol- and sphingolipid-enriched membrane domains that compartmentalize cellular processes. Small rafts can sometimes be stabilized to form larger platforms through protein-protein and protein-lipid interactions.
nuclear speck	A discrete extra-nucleolar subnuclear domain, 20-50 in number, in which splicing factors are seen to be localized by immunofluorescence microscopy.
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.
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.

4 GO annotations of molecular function

Name	Definition
identical protein binding	Binding to an identical protein or proteins.
SMAD binding	Binding to a SMAD signaling 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-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.

14 GO annotations of biological process

Name	Definition
negative regulation of BMP signaling pathway	Any process that stops, prevents, or reduces the frequency, rate or extent of the BMP signaling pathway.
negative regulation of transcription by RNA polymerase II	Any process that stops, prevents, or reduces the frequency, rate or extent of transcription mediated by RNA polymerase II.
negative regulation of transcription, DNA-templated	Any process that stops, prevents, or reduces the frequency, rate or extent of cellular DNA-templated transcription.
negative regulation of transforming growth factor beta receptor signaling pathway	Any process that stops, prevents, or reduces the frequency, rate or extent of any TGF-beta receptor signaling pathway.
positive regulation of canonical Wnt signaling pathway	Any process that increases the rate, frequency, or extent of the Wnt signaling pathway through beta-catenin, the series of molecular signals initiated by binding of a Wnt protein to a frizzled family receptor on the surface of the target cell, followed by propagation of the signal via beta-catenin, and ending with a change in transcription of target genes.
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 trophoblast cell migration	Any process that activates or increases the frequency, rate or extent of trophoblast cell migration.
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 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 transforming growth factor beta receptor signaling pathway	Any process that modulates the frequency, rate or extent of activity of any TGF-beta receptor signaling pathway.
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.
ubiquitin-dependent SMAD protein catabolic process	The chemical reactions and pathways resulting in the breakdown of SMAD signaling proteins by ubiquitination and targeting to the proteasome.
Wnt signaling pathway, planar cell polarity pathway	The series of molecular signals initiated by binding of a Wnt protein to a receptor on the surface of the target cell where activated receptors signal via downstream effectors including C-Jun N-terminal kinase (JNK) to modulate cytoskeletal elements and control cell polarity.

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
Q9Y0H4	Su(dx)	E3 ubiquitin-protein ligase Su	Drosophila melanogaster (Fruit fly)	SS
Q9V853	Smurf	E3 ubiquitin-protein ligase Smurf1	Drosophila melanogaster (Fruit fly)	SS
O95817	BAG3	BAG family molecular chaperone regulator 3	Homo sapiens (Human)	PR
O60861	GAS7	Growth arrest-specific protein 7	Homo sapiens (Human)	PR
Q9HCE7	SMURF1	E3 ubiquitin-protein ligase SMURF1	Homo sapiens (Human)	PR
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
O00308	WWP2	NEDD4-like E3 ubiquitin-protein ligase WWP2	Homo sapiens (Human)	EV
Q96PU5	NEDD4L	E3 ubiquitin-protein ligase NEDD4-like	Homo sapiens (Human)	PR
P46934	NEDD4	E3 ubiquitin-protein ligase NEDD4	Homo sapiens (Human)	EV
Q8IYU2	HACE1	E3 ubiquitin-protein ligase HACE1	Homo sapiens (Human)	EV
P46935	Nedd4	E3 ubiquitin-protein ligase NEDD4	Mus musculus (Mouse)	PR
Q9CUN6	Smurf1	E3 ubiquitin-protein ligase SMURF1	Mus musculus (Mouse)	PR
Q8BZZ3	Wwp1	NEDD4-like E3 ubiquitin-protein ligase WWP1	Mus musculus (Mouse)	SS
Q60780	Gas7	Growth arrest-specific protein 7	Mus musculus (Mouse)	PR
Q8C863	Itch	E3 ubiquitin-protein ligase Itchy	Mus musculus (Mouse)	EV
Q9DBH0	Wwp2	NEDD4-like E3 ubiquitin-protein ligase WWP2	Mus musculus (Mouse)	SS
Q8CFI0	Nedd4l	E3 ubiquitin-protein ligase NEDD4-like	Mus musculus (Mouse)	PR
A2A5Z6	Smurf2	E3 ubiquitin-protein ligase SMURF2	Mus musculus (Mouse)	SS
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
MSNPGGRRNG	PVKLRLTVLC	AKNLVKKDFF	RLPDPFAKVV	VDGSGQCHST	DTVKNTLDPK
70	80	90	100	110	120
WNQHYDLYIG	KSDSVTISVW	NHKKIHKKQG	AGFLGCVRLL	SNAINRLKDT	GYQRLDLCKL
130	140	150	160	170	180
GPNDNDTVRG	QIVVSLQSRD	RIGTGGQVVD	CSRLFDNDLP	DGWEERRTAS	GRIQYLNHIT
190	200	210	220	230	240
RTTQWERPTR	PASEYSSPGR	PLSCFVDENT	PISGTNGATC	GQSSDPRLAE	RRVRSQRHRN
250	260	270	280	290	300
YMSRTHLHTP	PDLPEGYEQR	TTQQGQVYFL	HTQTGVSTWH	DPRVPRDLSN	INCEELGPLP
310	320	330	340	350	360
PGWEIRNTAT	GRVYFVDHNN	RTTQFTDPRL	SANLHLVLNR	QNQLKDQQQQ	QVVSLCPDDT
370	380	390	400	410	420
ECLTVPRYKR	DLVQKLKILR	QELSQQQPQA	GHCRIEVSRE	EIFEESYRQV	MKMRPKDLWK
430	440	450	460	470	480
RLMIKFRGEE	GLDYGGVARE	WLYLLSHEML	NPYYGLFQYS	RDDIYTLQIN	PDSAVNPEHL
490	500	510	520	530	540
SYFHFVGRIM	GMAVFHGHYI	DGGFTLPFYK	QLLGKSITLD	DMELVDPDLH	NSLVWILEND
550	560	570	580	590	600
ITGVLDHTFC	VEHNAYGEII	QHELKPNGKS	IPVNEENKKE	YVRLYVNWRF	LRGIEAQFLA
610	620	630	640	650	660
LQKGFNEVIP	QHLLKTFDEK	ELELIICGLG	KIDVNDWKVN	TRLKHCTPDS	NIVKWFWKAV
670	680	690	700	710	720
EFFDEERRAR	LLQFVTGSSR	VPLQGFKALQ	GAAGPRLFTI	HQIDACTNNL	PKAHTCFNRI
730	740
DIPPYESYEK	LYEKLLTAIE	ETCGFAVE