AiPD: Autoinhibited Protein Database

Q13153

Gene name	PAK1
Protein name	Serine/threonine-protein kinase PAK 1
Names	Alpha-PAK, p21-activated kinase 1, PAK-1, p65-PAK
Species	Homo sapiens (Human)
KEGG Pathway	hsa:5058
EC number	2.7.11.1: Protein-serine/threonine kinases
Protein Class	SERINE/THREONINE-PROTEIN KINASE TAO (PTHR48015)

Descriptions

The p21-activated kinases (PAKs) control cytoskeletal actin assembly and activate Mes: (1) as an inactive homodimer in which kinase activity is autoinhibited by binding of the inhibitory segment of a second PAK molecule, and (2) as an active monomer.
Inhibitory segment hinders the kinase domain and stabilizes a disabled catalytic site, and thus limits the ability of each kinase to autophosphorylate, a required step for activation. Inhibitory segment is thought to exist in two states that are highly conserved in PAKs. PAKs are activated by the binding of GTP-loaded Cdc42 (or Rac) to the CRIB domain, which disrupts the dimer and unfolds the inhibitory segment. After releasing the inhibitory segment, the kinase domain is then autophosphorylated for full activation. In addition, phosphorylation of Ser residue (Ser144 of PAK1) in the inhibitory segment also significantly contributes to activation.
Alternative modes of activation that may not require GTPase binding have been described, but less understood, including binding of sphingosine, direct phosphorylation by AKT, PDK1, and JAK2, caspase-3 binding during apoptosis, and binding of PIX with subsequent recruitment to GIT1.

Autoinhibitory domains (AIDs)

Target domain	270-521 (Protein kinase domain)
Relief mechanism	Partner binding
Assay	Deletion assay, Mutagenesis experiment, Structural analysis

AID

137-149 (Inhibitory segment)

Target domain

270-521 (Protein kinase domain)

Relief mechanism

Partner binding (Binding of Cdc42 or Rac1 to CRIB domain)

Assay

Deletion assay, Mutagenesis experiment, Structural analysis

Accessory elements

406-429 (Activation loop from InterPro)

Target domain	270-521 (Protein kinase domain)
Relief mechanism
Assay

References

Lei M et al. (2000) "Structure of PAK1 in an autoinhibited conformation reveals a multistage activation switch", Cell, 102, 387-97

Totaro A et al. (2007) "Identification of an intramolecular interaction important for the regulation of GIT1 functions", Molecular biology of the cell, 18, 5124-38

Bautista L et al. (2020) "p21-Activated Kinases in Thyroid Cancer", Endocrinology, 161,

Chong C et al. (2001) "The mechanism of PAK activation. Autophosphorylation events in both regulatory and kinase domains control activity", The Journal of biological chemistry, 276, 17347-53

Wang J et al. (2011) "Structural insights into the autoactivation mechanism of p21-activated protein kinase", Structure (London, England : 1993), 19, 1752-61

Ha BH et al. (2012) "Type II p21-activated kinases (PAKs) are regulated by an autoinhibitory pseudosubstrate", Proceedings of the National Academy of Sciences of the United States of America, 109, 16107-12

Autoinhibited structure

Activated structure

33 structures for Q13153

Entry ID	Method	Resolution	Chain	Position	Source
1F3M	X-ray	230 A			PDB
1YHV	X-ray	180 A	A	249-545	PDB
1YHW	X-ray	180 A	A	249-545	PDB
1ZSG	NMR	-	B	183-204	PDB
2HY8	X-ray	200 A	1	249-545	PDB
2QME	X-ray	175 A	I	74-109	PDB
3DVP	X-ray	250 A	C/D	212-221	PDB
3FXZ	X-ray	164 A	A	249-545	PDB
3FY0	X-ray	235 A	A	249-545	PDB
3Q4Z	X-ray	189 A	A/B	248-545	PDB
3Q52	X-ray	180 A	A	248-545	PDB
3Q53	X-ray	209 A	A	248-545	PDB
4DAW	X-ray	200 A	A	249-545	PDB
4EQC	X-ray	201 A	A	249-545	PDB
4O0R	X-ray	240 A	A/B	249-545	PDB
4O0T	X-ray	260 A	A/B	249-545	PDB
4P90	X-ray	249 A	A/B	249-545	PDB
4ZJI	X-ray	199 A	A/B/C/D	249-545	PDB
4ZJJ	X-ray	220 A	A/B/C/D	249-545	PDB
4ZLO	X-ray	250 A	A/B	249-545	PDB
4ZY4	X-ray	260 A	A/B	249-545	PDB
4ZY5	X-ray	235 A	A/B	249-545	PDB
4ZY6	X-ray	215 A	A/B	249-545	PDB
5DEW	X-ray	190 A	A/B	249-545	PDB
5DEY	X-ray	210 A	A/B	249-545	PDB
5DFP	X-ray	220 A	A	249-545	PDB
5IME	X-ray	222 A	A/B	249-545	PDB
5KBQ	X-ray	258 A	A/B	254-542	PDB
5KBR	X-ray	236 A	A/B	254-542	PDB
6B16	X-ray	229 A	A/B	249-545	PDB
7VTO	X-ray	259 A	A/B	249-545	PDB
8X5Z	X-ray	180 A	A	249-545	PDB
AF-Q13153-F1	Predicted				AlphaFoldDB

212 variants for Q13153

Variant ID(s)	Position	Change	Description	Diseaes Association	Provenance
rs1949519149 RCV001806087 RCV001249699	121	P>L	PAK1-related neurodevelopmental disorders [ClinVar]	Yes	ClinVar dbSNP
RCV000714509 CA382169543 VAR_081554 rs1565638316	131	Y>C	IDDMSSD; gain of function; enhanced PAK1 kinase activity and significantly reduced homodimerization Intellectual developmental disorder with macrocephaly, seizures, and speech delay [UniProt, ClinVar]	Yes	ClinGen ClinVar UniProt Ensembl dbSNP
RCV001256037 rs767363828 CA6200020	272	R>W	Intellectual disability [ClinVar]	Yes	ClinGen ClinVar ExAC TOPMed dbSNP gnomAD
RCV001266426 rs1942667410	409	G>R	Inborn genetic diseases [ClinVar]	Yes	ClinVar dbSNP
rs1565583382 RCV000714510 CA382093103 VAR_081555	429	Y>C	IDDMSSD; gain-of-function; enhanced PAK1 kinase activity and significantly reduced homodimerization Intellectual developmental disorder with macrocephaly, seizures, and speech delay [UniProt, ClinVar]	Yes	ClinGen ClinVar UniProt Ensembl dbSNP
rs1942648391 RCV001262617	470	L>R	Intellectual developmental disorder with macrocephaly, seizures, and speech delay [ClinVar]	Yes	ClinVar dbSNP
CA382092449 rs1591695781 RCV000995827	476	I>T	Intellectual developmental disorder with macrocephaly, seizures, and speech delay [ClinVar]	Yes	ClinGen ClinVar Ensembl dbSNP
rs757020946 RCV001253499	495	R>G	Intellectual developmental disorder with macrocephaly, seizures, and speech delay [ClinVar]	Yes	ClinVar dbSNP
rs111649865 CA225037344	2	S>*		No	ClinGen Ensembl
rs111649865 CA225037343	2	S>*		No	ClinGen Ensembl
CA6200207 rs61729072	4	N>S		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs556454039 CA6200206	5	G>D		No	ClinGen 1000Genomes ExAC gnomAD
CA382171902 rs1214886996	5	G>S		No	ClinGen gnomAD
rs1361179730 CA382171879	6	L>P		No	ClinGen TOPMed
rs1226576738 CA382171861	7	D>G		No	ClinGen gnomAD
CA6200203 rs200229390	8	I>S		No	ClinGen ExAC gnomAD
rs1438267597 CA382171836	9	Q>*		No	ClinGen gnomAD
CA225037342 rs373250446	9	Q>R		No	ClinGen ESP TOPMed
rs150830172 CA225037341	10	D>E		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
rs1323346373 CA382171799	11	K>E		No	ClinGen gnomAD
CA6200201 rs763083619	11	K>N		No	ClinGen ExAC gnomAD
CA382171793 rs1410916201	11	K>R		No	ClinGen gnomAD
CA382171750 rs1395768376	13	P>L		No	ClinGen gnomAD
CA382171705 rs1223455923	16	P>L		No	ClinGen TOPMed
rs1592197974 CA382171599	22	T>A		No	ClinGen Ensembl
CA382171579 rs1439397121	23	M>K		No	ClinGen gnomAD
rs199962205 CA225037339	23	M>V		No	ClinGen 1000Genomes gnomAD
rs1270608708 CA382171544	24	I>T		No	ClinGen gnomAD
CA382171515 rs1195228497	26	A>S		No	ClinGen gnomAD
rs1048521 CA225037338	26	A>V		No	ClinGen Ensembl
CA225037337 rs996658283	27	G>S		No	ClinGen TOPMed gnomAD
rs1231385297 CA382171484	27	G>V		No	ClinGen TOPMed gnomAD
rs1443904811 CA382171358	36	H>R		No	ClinGen gnomAD
rs997423059 CA225037335	37	G>S		No	ClinGen TOPMed
rs1429686380 CA382171143	51	K>M		No	ClinGen gnomAD
rs748471279 CA6200192	56	R>*		No	ClinGen ExAC gnomAD
CA6200191 rs779686585	60	P>H		No	ClinGen ExAC gnomAD
CA382171076 rs779686585	60	P>L		No	ClinGen ExAC gnomAD
CA382170108 rs1406013685	67	K>N		No	ClinGen gnomAD
rs1272985698 CA382170093	69	E>D		No	ClinGen TOPMed
rs779171013 CA6200172	72	R>W		No	ClinGen ExAC TOPMed gnomAD
CA382170065 rs1354646218	74	E>K		No	ClinGen gnomAD
COSM110331 CA225036041 rs144273203	79	S>L	skin [Cosmic]	No	ClinGen cosmic curated Ensembl
rs1253068227 CA382170026	80	D>H		No	ClinGen TOPMed
rs1314801161 CA382169949	90	D>V		No	ClinGen TOPMed gnomAD
rs745562907 CA6200169	91	A>S		No	ClinGen ExAC gnomAD
CA382169935 rs1374612097	93	T>A		No	ClinGen TOPMed
CA382169920 rs1394298279	95	E>A		No	ClinGen TOPMed
rs956235500 CA225036040	97	T>M		No	ClinGen Ensembl
COSM1243479 COSM1243478 CA6200151 rs769079461	105	R>C	oesophagus [Cosmic]	No	ClinGen cosmic curated ExAC TOPMed gnomAD
RCV001171663 rs937721392 CA225035987	105	R>H		No	ClinGen ClinVar TOPMed dbSNP gnomAD
CA6200148 rs369339512	115	S>L		No	ClinGen ESP ExAC gnomAD
rs1365021458 CA382169633	122	Q>*		No	ClinGen TOPMed
CA382169587 rs1164040392	126	D>H		No	ClinGen TOPMed gnomAD
rs778753573 CA6200143	132	N>D		No	ClinGen ExAC gnomAD
CA382169528 rs1196615739 COSM225317	133	S>L	NS [Cosmic]	No	ClinGen cosmic curated TOPMed
CA382169501 rs1565638248	135	K>N		No	ClinGen Ensembl
CA6200142 rs754759788	136	T>K		No	ClinGen ExAC gnomAD
RCV001091736 rs1949512290	143	M>K		No	ClinVar dbSNP
RCV001268614 rs1949512290	143	M>T		No	ClinVar dbSNP
CA382169403 rs1214376227	146	T>R		No	ClinGen TOPMed
CA225035509 rs963508717	147	D>G		No	ClinGen TOPMed gnomAD
CA382169398 rs1207248741	147	D>Y		No	ClinGen gnomAD
rs756375271 CA6200120	148	K>N		No	ClinGen ExAC gnomAD
CA382168976 rs1284868465	149	S>P		No	ClinGen TOPMed
CA6200119 rs750682827	150	A>T		No	ClinGen ExAC gnomAD
rs1349619138 CA382168958	150	A>V		No	ClinGen gnomAD
CA382168950 rs1313468979	151	E>G		No	ClinGen gnomAD
CA6200118 rs138404683	154	N>S		No	ClinGen ESP ExAC TOPMed gnomAD
rs138404683 CA382168904	154	N>T		No	ClinGen ESP ExAC TOPMed gnomAD
CA382168886 rs1276198531	155	S>F		No	ClinGen TOPMed
rs1037475719 CA225035508	156	S>Y		No	ClinGen Ensembl
CA382168844 rs1365138159	159	L>S		No	ClinGen gnomAD
rs1454012088 CA382168848	159	L>V		No	ClinGen gnomAD
rs1367196639 CA382167920	164	V>G		No	ClinGen gnomAD
CA225034019 rs145756161	164	V>M		No	ClinGen ESP TOPMed
CA382167884 rs1447705311	167	T>I		No	ClinGen gnomAD
CA6200096 rs149432352	168	P>H		No	ClinGen ESP ExAC TOPMed gnomAD
CA6200097 rs777870573	168	P>S		No	ClinGen ExAC gnomAD
rs753260953 CA382167865	169	A>P		No	ClinGen ExAC gnomAD
rs753260953 CA6200095	169	A>S		No	ClinGen ExAC gnomAD
CA6200092 rs374488307	172	P>L		No	ClinGen ESP ExAC
CA382167816 rs767025994	173	V>F		No	ClinGen ExAC TOPMed gnomAD
CA6200091 rs767025994	173	V>L		No	ClinGen ExAC TOPMed gnomAD
rs1565612949 CA382167789	175	E>A		No	ClinGen Ensembl
rs866570863 CA225034018	178	D>E		No	ClinGen Ensembl
rs1565612875 CA382167707	184	A>D		No	ClinGen Ensembl
CA6200086 rs773970537	185	T>I		No	ClinGen ExAC gnomAD
rs768350096 CA6200085	186	P>L		No	ClinGen ExAC TOPMed gnomAD
rs768350096 CA382167688	186	P>Q		No	ClinGen ExAC TOPMed gnomAD
COSM4146348 CA382167690 rs1401264540 COSM4146349	186	P>S	thyroid [Cosmic]	No	ClinGen cosmic curated gnomAD
rs1401264540 CA382167693	186	P>T		No	ClinGen gnomAD
rs762974726 CA6200084	191	A>V		No	ClinGen ExAC
rs370942329 CA6200083	193	R>C		No	ClinGen ESP ExAC TOPMed gnomAD
CA382167613 rs1221370333	193	R>H		No	ClinGen Ensembl
rs1371992913 CA382167562	198	K>R		No	ClinGen TOPMed
CA6200064 rs775172015	201	Y>H		No	ClinGen ExAC TOPMed gnomAD
rs765038017 CA6200063	203	R>Q		No	ClinGen ExAC gnomAD
CA382167513 rs1200382364	204	S>C		No	ClinGen TOPMed gnomAD
CA6200062 rs759569169	206	I>S		No	ClinGen ExAC
CA382167492 rs1348053573	207	E>D		No	ClinGen gnomAD
CA6200061 rs776284597	213	P>A		No	ClinGen ExAC gnomAD
CA225033757 rs201772083	215	R>P		No	ClinGen TOPMed gnomAD
CA382167449 rs201772083	215	R>Q		No	ClinGen TOPMed gnomAD
CA225033758 rs887262054	215	R>W		No	ClinGen TOPMed
CA6200059 rs773354843	217	V>L		No	ClinGen ExAC TOPMed gnomAD
CA6200058 rs773354843	217	V>M		No	ClinGen ExAC TOPMed gnomAD
CA6200057 rs150302040	219	T>A		No	ClinGen ESP ExAC TOPMed
CA382167423 rs1346690686	220	S>P		No	ClinGen TOPMed
CA6200055 rs779095416	221	P>S		No	ClinGen ExAC gnomAD
CA382167412 rs1319725019	222	I>V		No	ClinGen TOPMed
rs1591881794 CA382167399	224	P>A		No	ClinGen Ensembl
CA225033755 rs1039659377	225	T>A		No	ClinGen TOPMed
CA6200053 rs200829185	226	E>A		No	ClinGen 1000Genomes ExAC TOPMed gnomAD
rs1286223691 CA382167373	228	N>D		No	ClinGen TOPMed
CA6200052 rs780271453	230	T>A		No	ClinGen ExAC TOPMed gnomAD
CA6200051 rs756493654	234	A>V		No	ClinGen ExAC gnomAD
CA382167324 rs1181453821	235	L>F		No	ClinGen gnomAD
CA382167317 rs750826465	237	R>G		No	ClinGen ExAC TOPMed gnomAD
CA225033752 rs1048522	237	R>L		No	ClinGen ExAC TOPMed gnomAD
rs1048522 CA6200049	237	R>Q		No	ClinGen ExAC TOPMed gnomAD
CA6200050 rs750826465	237	R>W		No	ClinGen ExAC TOPMed gnomAD
rs1207365793 CA382167315	238	N>H		No	ClinGen gnomAD
rs1368727961 CA382167297	240	E>G		No	ClinGen TOPMed
rs776571998 CA382167257	245	K>N		No	ClinGen ExAC gnomAD
CA6200046 rs764844044	245	K>Q		No	ClinGen ExAC gnomAD
rs759377668 CA6200045	245	K>R		No	ClinGen ExAC gnomAD
rs1356610370 CA382167248	247	K>E		No	ClinGen gnomAD
rs1445967556 CA382167234	248	M>I		No	ClinGen gnomAD
rs1304697598 CA382167237	248	M>T		No	ClinGen gnomAD
rs1565608964 CA382167240	248	M>V		No	ClinGen Ensembl
CA382167214 rs1319295411	250	D>G		No	ClinGen gnomAD
rs773010540 CA6200040	253	I>T		No	ClinGen ExAC gnomAD
CA382167165 rs1415925013	254	L>S		No	ClinGen gnomAD
CA225033749 rs201726311 COSM1152404 COSM196508	258	R>*	large_intestine endometrium [Cosmic]	No	ClinGen cosmic curated Ensembl
rs1392857529 CA382166805	265	D>N		No	ClinGen TOPMed
CA6200022 rs760651558	269	K>R		No	ClinGen ExAC gnomAD
rs756926780 CA225033540	272	R>Q		No	ClinGen gnomAD
CA225033539 rs376464787	276	I>T		No	ClinGen ESP TOPMed
rs767459594 CA6200002	281	S>L		No	ClinGen ExAC gnomAD
rs1173654967 CA382165980	283	T>A		No	ClinGen gnomAD
CA382165981 rs1173654967	283	T>P		No	ClinGen gnomAD
rs1375612113 CA382165960	286	T>A		No	ClinGen gnomAD
CA6199999 rs764328411	288	M>I		No	ClinGen ExAC
rs1433026893 CA382165948	288	M>V		No	ClinGen gnomAD
CA382165902 rs1252984177	294	Q>H		No	ClinGen gnomAD
rs111242254 CA225033111	295	E>G		No	ClinGen gnomAD
CA382165431 rs1218565666	298	I>V		No	ClinGen TOPMed
rs748528205 CA6199971	304	Q>H		No	ClinGen ExAC gnomAD
CA6199970 rs775060240	307	P>S		No	ClinGen ExAC gnomAD
COSM1509971 rs769471788 CA382165341 COSM1509970	310	E>*	lung [Cosmic]	No	ClinGen cosmic curated ExAC gnomAD
CA6199969 rs769471788	310	E>K		No	ClinGen ExAC gnomAD
CA382165315 rs1485272225	314	N>D		No	ClinGen TOPMed
rs906897096 CA225032590	320	R>K		No	ClinGen Ensembl
rs1036041813 CA225032589	322	N>K		No	ClinGen TOPMed gnomAD
CA382165250 rs1565593470	323	K>Q		No	ClinGen Ensembl
CA382165234 rs1389156966	325	P>A		No	ClinGen gnomAD
rs1475327879 CA382165225	326	N>T		No	ClinGen TOPMed
CA225032286 rs534472752	336	V>M		No	ClinGen gnomAD
CA225032285 rs1031591829	351	S>P		No	ClinGen TOPMed gnomAD
CA6199954 rs762128146	355	V>L		No	ClinGen ExAC gnomAD
rs1174509789 CA382164541	362	D>G		No	ClinGen TOPMed gnomAD
CA382164540 rs1174509789	362	D>V		No	ClinGen TOPMed gnomAD
CA382164480 rs1483962098	371	R>C		No	ClinGen gnomAD
CA6199951 rs145870074	371	R>H		No	ClinGen ESP ExAC gnomAD
rs1352872191 CA382093489	376	A>P		No	ClinGen TOPMed
CA382093472 rs1287187981	378	E>D		No	ClinGen TOPMed
rs772100439 CA6199928	382	S>A		No	ClinGen ExAC gnomAD
rs1326439583 CA382093444	382	S>L		No	ClinGen TOPMed
CA6199925 rs200382044	383	N>S		No	ClinGen ExAC TOPMed gnomAD
CA382093298 rs1415355342	403	V>I		No	ClinGen gnomAD
rs1488995878 CA382093262	406	T>I		No	ClinGen gnomAD
CA382093205 rs1220894154	414	I>T		No	ClinGen gnomAD
rs1358902848 CA382093201	415	T>A		No	ClinGen gnomAD
CA382093191 rs1275366470	416	P>L		No	ClinGen TOPMed gnomAD
rs1233155113 CA382093157	421	R>Q		No	ClinGen TOPMed
CA224853865 rs972319037	421	R>W		No	ClinGen TOPMed
rs1330569336 CA382093117	427	T>S		No	ClinGen TOPMed
rs781239784 CA6199901	433	P>S		No	ClinGen ExAC gnomAD
rs757273330 CA6199900	434	E>K		No	ClinGen ExAC gnomAD
CA382093061 rs1444868571	435	V>F		No	ClinGen TOPMed
rs747098916 CA6199899	438	R>*		No	ClinGen ExAC TOPMed gnomAD
CA6199898 rs778201116	440	A>P		No	ClinGen ExAC TOPMed gnomAD
rs778201116 CA382093032	440	A>S		No	ClinGen ExAC TOPMed gnomAD
rs752969852 CA6199896	444	K>N		No	ClinGen ExAC gnomAD
rs1473604815 CA382092960	451	G>S		No	ClinGen TOPMed
CA382092888 rs1295084887	460	G>A		No	ClinGen Ensembl
CA6199893 rs750033937	461	E>*		No	ClinGen ExAC gnomAD
CA6199878 rs748742535	479	N>S		No	ClinGen ExAC gnomAD
rs866912232 CA224852729	482	P>S		No	ClinGen Ensembl
rs779301516 CA6199877	486	N>H		No	ClinGen ExAC TOPMed gnomAD
rs754285391 CA6199875	492	A>G		No	ClinGen ExAC gnomAD
CA224852703 rs969130942	493	I>V		No	ClinGen TOPMed gnomAD
CA6199872 rs751082909	495	R>Q		No	ClinGen ExAC TOPMed gnomAD
CA6199873 rs757020946	495	R>W		No	ClinGen ExAC TOPMed gnomAD
CA382092326 rs1022775226	496	D>H		No	ClinGen TOPMed gnomAD
rs1022775226 CA224852697	496	D>N		No	ClinGen TOPMed gnomAD
rs115181854 CA6199870	500	R>C		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA382092297 rs115181854	500	R>G		No	ClinGen 1000Genomes ESP ExAC TOPMed gnomAD
CA6199869 rs752626713	500	R>H		No	ClinGen ExAC TOPMed gnomAD
rs371644543 COSM326056 CA6199866	503	E>K	lung [Cosmic]	No	ClinGen cosmic curated ESP ExAC TOPMed gnomAD
CA382092231 rs1459381149	509	R>K		No	ClinGen TOPMed
CA6199864 rs760950250	513	K>E		No	ClinGen ExAC gnomAD
rs35345144 VAR_051654 CA224852669	515	L>V		No	ClinGen UniProt Ensembl dbSNP
CA224852666 rs148485752	517	Q>R		No	ClinGen ESP
CA224850213 rs145609626	525	K>E		No	ClinGen ESP
rs376164226 CA6199815	527	L>H		No	ClinGen ESP ExAC TOPMed gnomAD
rs754414858 CA6199813	537	A>P		No	ClinGen ExAC gnomAD
rs1279823956 CA382091335	539	E>D		No	ClinGen gnomAD
CA224850209 rs917123146	540	A>P		No	ClinGen Ensembl
rs1321832144 CA382091302	544	N>S		No	ClinGen gnomAD
CA6199811 rs779918198	545	H>Q		No	ClinGen ExAC gnomAD

1 associated diseases with Q13153

[MIM: 618158]: Intellectual developmental disorder with macrocephaly, seizures, and speech delay (IDDMSSD)

An autosomal dominant neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures. {ECO:0000269|PubMed:30290153}. Note=The disease is caused by variants affecting the gene represented in this entry.

Without disease ID

An autosomal dominant neurodevelopmental disorder characterized by impaired intellectual development, poor speech, postnatal macrocephaly, and seizures. {ECO:0000269|PubMed:30290153}. Note=The disease is caused by variants affecting the gene represented in this entry.

5 regional properties for Q13153

Type	Name	Position	InterPro Accession
domain	CRIB domain	74 - 132	IPR000095
domain	Protein kinase domain	270 - 521	IPR000719
active_site	Serine/threonine-protein kinase, active site	385 - 397	IPR008271
binding_site	Protein kinase, ATP binding site	276 - 299	IPR017441
domain	p21 activated kinase binding domain	73 - 118	IPR033923

Functions

		Description
EC Number	2.7.11.1	Protein-serine/threonine kinases
Subcellular Localization	Cytoplasm Cell junction, focal adhesion Cell projection, lamellipodium Cell membrane Cell projection, ruffle membrane Cell projection, invadopodium Nucleus, nucleoplasm Chromosome Cytoplasm, cytoskeleton, microtubule organizing center, centrosome	Colocalizes with RUFY3, F-actin and other core migration components in invadopodia at the cell periphery (PubMed:25766321) Recruited to the cell membrane by interaction with CDC42 and RAC1 Recruited to focal adhesions upon activation Colocalized with CIB1 within membrane ruffles during cell spreading upon readhesion to fibronectin Upon DNA damage, translocates to the nucleoplasm when phosphorylated at Thr-212 where is co-recruited with MORC2 on damaged chromatin (PubMed:23260667) Localization to the centrosome does not depend upon the presence of gamma-tubulin (PubMed:27012601) Localization of the active, but not inactive, protein to the adhesions and edge of lamellipodia is mediated by interaction with GIT1 (PubMed:11896197)
PANTHER Family	PTHR48015	SERINE/THREONINE-PROTEIN KINASE TAO
PANTHER Subfamily	PTHR48015:SF20	SERINE_THREONINE-PROTEIN KINASE PAK 1
PANTHER Protein Class	non-receptor serine/threonine protein kinase protein modifying enzyme
PANTHER Pathway Category	Axon guidance mediated by semaphorins PAK Inflammation mediated by chemokine and cytokine signaling pathway PAK Cytoskeletal regulation by Rho GTPase PAK CCKR signaling map PAK CCKR signaling map PAK1 T cell activation PAK Angiogenesis PAK Ras Pathway PAK

18 GO annotations of cellular component

Name	Definition
actin filament	A filamentous structure formed of a two-stranded helical polymer of the protein actin and associated proteins. Actin filaments are a major component of the contractile apparatus of skeletal muscle and the microfilaments of the cytoskeleton of eukaryotic cells. The filaments, comprising polymerized globular actin molecules, appear as flexible structures with a diameter of 5-9 nm. They are organized into a variety of linear bundles, two-dimensional networks, and three dimensional gels. In the cytoskeleton they are most highly concentrated in the cortex of the cell just beneath the plasma membrane.
axon	The long process of a neuron that conducts nerve impulses, usually away from the cell body to the terminals and varicosities, which are sites of storage and release of neurotransmitter.
cell-cell junction	A cell junction that forms a connection between two or more cells of an organism; excludes direct cytoplasmic intercellular bridges, such as ring canals in insects.
chromosome	A structure composed of a very long molecule of DNA and associated proteins (e.g. histones) that carries hereditary information.
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.
dendrite	A neuron projection that has a short, tapering, morphology. Dendrites receive and integrate signals from other neurons or from sensory stimuli, and conduct nerve impulses towards the axon or the cell body. In most neurons, the impulse is conveyed from dendrites to axon via the cell body, but in some types of unipolar neuron, the impulse does not travel via the cell body.
focal adhesion	A cell-substrate junction that anchors the cell to the extracellular matrix and that forms a point of termination of actin filaments. In insects focal adhesion has also been referred to as hemi-adherens junction (HAJ).
intercalated disc	A complex cell-cell junction at which myofibrils terminate in cardiomyocytes; mediates mechanical and electrochemical integration between individual cardiomyocytes. The intercalated disc contains regions of tight mechanical attachment (fasciae adherentes and desmosomes) and electrical coupling (gap junctions) between adjacent cells.
lamellipodium	A thin sheetlike process extended by the leading edge of a migrating cell or extending cell process; contains a dense meshwork of actin filaments.
microtubule organizing center	An intracellular structure that can catalyze gamma-tubulin-dependent microtubule nucleation and that can anchor microtubules by interacting with their minus ends, plus ends or sides.
nuclear membrane	Either of the lipid bilayers that surround the nucleus and form the nuclear envelope; excludes the intermembrane space.
nucleoplasm	That part of the nuclear content other than the chromosomes or the nucleolus.
plasma membrane	The membrane surrounding a cell that separates the cell from its external environment. It consists of a phospholipid bilayer and associated proteins.
protein-containing complex	A stable assembly of two or more macromolecules, i.e. proteins, nucleic acids, carbohydrates or lipids, in which at least one component is a protein and the constituent parts function together.
ruffle	Projection at the leading edge of a crawling cell; the protrusions are supported by a microfilament meshwork.
ruffle membrane	The portion of the plasma membrane surrounding a ruffle.
Z disc	Platelike region of a muscle sarcomere to which the plus ends of actin filaments are attached.

8 GO annotations of molecular function

Name	Definition
ATP binding	Binding to ATP, adenosine 5'-triphosphate, a universally important coenzyme and enzyme regulator.
collagen binding	Binding to collagen, a group of fibrous proteins of very high tensile strength that form the main component of connective tissue in animals. Collagen is highly enriched in glycine (some regions are 33% glycine) and proline, occurring predominantly as 3-hydroxyproline (about 20%).
gamma-tubulin binding	Binding to the microtubule constituent protein gamma-tubulin.
identical protein binding	Binding to an identical protein or proteins.
protein kinase activity	Catalysis of the phosphorylation of an amino acid residue in a protein, usually according to the reaction: a protein + ATP = a phosphoprotein + ADP.
protein serine kinase activity	Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate.
protein serine/threonine kinase activity	Catalysis of the reactions: ATP + protein serine = ADP + protein serine phosphate, and ATP + protein threonine = ADP + protein threonine phosphate.
protein serine/threonine/tyrosine kinase activity	Catalysis of the reactions: ATP + a protein serine = ADP + protein serine phosphate; ATP + a protein threonine = ADP + protein threonine phosphate; and ATP + a protein tyrosine = ADP + protein tyrosine phosphate.

30 GO annotations of biological process

Name	Definition
actin cytoskeleton reorganization	A process that is carried out at the cellular level which results in dynamic structural changes to the arrangement of constituent parts of cytoskeletal structures comprising actin filaments and their associated proteins.
apoptotic process	A programmed cell death process which begins when a cell receives an internal (e.g. DNA damage) or external signal (e.g. an extracellular death ligand), and proceeds through a series of biochemical events (signaling pathway phase) which trigger an execution phase. The execution phase is the last step of an apoptotic process, and is typically characterized by rounding-up of the cell, retraction of pseudopodes, reduction of cellular volume (pyknosis), chromatin condensation, nuclear fragmentation (karyorrhexis), plasma membrane blebbing and fragmentation of the cell into apoptotic bodies. When the execution phase is completed, the cell has died.
branching morphogenesis of an epithelial tube	The process in which the anatomical structures of branches in an epithelial tube are generated and organized. A tube is a long hollow cylinder.
cell migration	The controlled self-propelled movement of a cell from one site to a destination guided by molecular cues. Cell migration is a central process in the development and maintenance of multicellular organisms.
cellular response to DNA damage stimulus	Any process that results in a change in state or activity of a cell (in terms of movement, secretion, enzyme production, gene expression, etc.) as a result of a stimulus indicating damage to its DNA from environmental insults or errors during metabolism.
chromatin remodeling	A dynamic process of chromatin reorganization resulting in changes to chromatin structure. These changes allow DNA metabolic processes such as transcriptional regulation, DNA recombination, DNA repair, and DNA replication.
ephrin receptor signaling pathway	The series of molecular signals initiated by ephrin binding to its receptor, and ending with the regulation of a downstream cellular process, e.g. transcription.
exocytosis	A process of secretion by a cell that results in the release of intracellular molecules (e.g. hormones, matrix proteins) contained within a membrane-bounded vesicle. Exocytosis can occur either by full fusion, when the vesicle collapses into the plasma membrane, or by a kiss-and-run mechanism that involves the formation of a transient contact, a pore, between a granule (for exemple of chromaffin cells) and the plasma membrane. The latter process most of the time leads to only partial secretion of the granule content. Exocytosis begins with steps that prepare vesicles for fusion with the membrane (tethering and docking) and ends when molecules are secreted from the cell.
Fc-gamma receptor signaling pathway involved in phagocytosis	An Fc-gamma receptor signaling pathway that contributes to the endocytic engulfment of external particulate material by phagocytes.
hepatocyte growth factor receptor signaling pathway	The series of molecular signals initiated by a ligand binding to a hepatocyte growth factor receptor, and ending with the regulation of a downstream cellular process, e.g. transcription.
intracellular signal transduction	The process in which a signal is passed on to downstream components within the cell, which become activated themselves to further propagate the signal and finally trigger a change in the function or state of the cell.
negative regulation of cell proliferation involved in contact inhibition	Any process that stops, prevents or reduces the rate or extent of cell proliferation in response to cell density.
neuron projection morphogenesis	The process in which the anatomical structures of a neuron projection are generated and organized. A neuron projection is any process extending from a neural cell, such as axons or dendrites.
phosphorylation	The process of introducing a phosphate group into a molecule, usually with the formation of a phosphoric ester, a phosphoric anhydride or a phosphoric amide.
positive regulation of cell migration	Any process that activates or increases the frequency, rate or extent of cell migration.
positive regulation of cell population proliferation	Any process that activates or increases the rate or extent of cell proliferation.
positive regulation of intracellular estrogen receptor signaling pathway	Any process that activates or increases the frequency, rate or extent of the activity of an intracellular estrogen receptor signaling pathway.
positive regulation of JUN kinase activity	Any process that activates or increases the frequency, rate or extent of JUN kinase activity.
positive regulation of microtubule nucleation	Any process that increases the rate, frequency or extent of microtubule nucleation. Microtubule nucleation is the 'de novo' formation of a microtubule, in which tubulin heterodimers form metastable oligomeric aggregates, some of which go on to support formation of a complete microtubule. Microtubule nucleation usually occurs from a specific site within a cell.
positive regulation of microtubule polymerization	Any process that activates or increases the frequency, rate or extent of microtubule polymerization.
positive regulation of peptidyl-serine phosphorylation	Any process that activates or increases the frequency, rate or extent of the phosphorylation of peptidyl-serine.
positive regulation of protein phosphorylation	Any process that activates or increases the frequency, rate or extent of addition of phosphate groups to amino acids within a protein.
positive regulation of stress fiber assembly	Any process that activates or increases the frequency, rate or extent of the assembly of a stress fiber, a bundle of microfilaments and other proteins found in fibroblasts.
protein autophosphorylation	The phosphorylation by a protein of one or more of its own amino acid residues (cis-autophosphorylation), or residues on an identical protein (trans-autophosphorylation).
protein phosphorylation	The process of introducing a phosphate group on to a protein.
regulation of actin cytoskeleton organization	Any process that modulates the frequency, rate or extent of the formation, arrangement of constituent parts, or disassembly of cytoskeletal structures comprising actin filaments and their associated proteins.
regulation of axonogenesis	Any process that modulates the frequency, rate or extent of axonogenesis, the generation of an axon, the long process of a neuron.
regulation of MAPK cascade	Any process that modulates the frequency, rate or extent of signal transduction mediated by the MAP kinase (MAPK) cascade.
stimulatory C-type lectin receptor signaling pathway	The series of molecular signals initiated by the binding of C-type lectin to its receptor on the surface of a target cell, and resulting in cellular activation.
wound healing	The series of events that restore integrity to a damaged tissue, following an injury.

24 homologous proteins in AiPD

UniProt AC	Gene Name	Protein Name	Species	Evidence Code
Q12469	SKM1	Serine/threonine-protein kinase SKM1	Saccharomyces cerevisiae (strain ATCC 204508 / S288c) (Baker's yeast)	PR
Q08E52	PAK1	Serine/threonine-protein kinase PAK 1	Bos taurus (Bovine)	SS
Q7YQL4	PAK3	Serine/threonine-protein kinase PAK 3	Pan troglodytes (Chimpanzee)	SS
Q9VXE5	mbt	Serine/threonine-protein kinase PAK mbt	Drosophila melanogaster (Fruit fly)	PR
Q13043	STK4	Serine/threonine-protein kinase 4	Homo sapiens (Human)	EV
Q13188	STK3	Serine/threonine-protein kinase 3	Homo sapiens (Human)	SS
Q9NQU5	PAK6	Serine/threonine-protein kinase PAK 6	Homo sapiens (Human)	EV
Q9P286	PAK5	Serine/threonine-protein kinase PAK 5	Homo sapiens (Human)	EV
O96013	PAK4	Serine/threonine-protein kinase PAK 4	Homo sapiens (Human)	EV
Q13177	PAK2	Serine/threonine-protein kinase PAK 2	Homo sapiens (Human)	EV
O75914	PAK3	Serine/threonine-protein kinase PAK 3	Homo sapiens (Human)	SS
O95819	MAP4K4	Mitogen-activated protein kinase kinase kinase kinase 4	Homo sapiens (Human)	PR
Q8C015	Pak5	Serine/threonine-protein kinase PAK 5	Mus musculus (Mouse)	SS
Q3ULB5	Pak6	Serine/threonine-protein kinase PAK 6	Mus musculus (Mouse)	PR
Q61036	Pak3	Serine/threonine-protein kinase PAK 3	Mus musculus (Mouse)	SS
Q8CIN4	Pak2	Serine/threonine-protein kinase PAK 2	Mus musculus (Mouse)	SS
O88643	Pak1	Serine/threonine-protein kinase PAK 1	Mus musculus (Mouse)	SS
Q62829	Pak3	Serine/threonine-protein kinase PAK 3	Rattus norvegicus (Rat)	SS
D4A280	Pak5	Serine/threonine-protein kinase PAK 5	Rattus norvegicus (Rat)	SS
Q64303	Pak2	Serine/threonine-protein kinase PAK 2	Rattus norvegicus (Rat)	SS
P35465	Pak1	Serine/threonine-protein kinase PAK 1	Rattus norvegicus (Rat)	SS
G5EFU0	pak-2	Serine/threonine-protein kinase pak-2	Caenorhabditis elegans	PR
Q17850	pak-1	Serine/threonine-protein kinase pak-1	Caenorhabditis elegans	PR
G5EGQ3	max-2	Serine/threonine-protein kinase max-2	Caenorhabditis elegans	SS

10	20	30	40	50	60
MSNNGLDIQD	KPPAPPMRNT	STMIGAGSKD	AGTLNHGSKP	LPPNPEEKKK	KDRFYRSILP
70	80	90	100	110	120
GDKTNKKKEK	ERPEISLPSD	FEHTIHVGFD	AVTGEFTGMP	EQWARLLQTS	NITKSEQKKN
130	140	150	160	170	180
PQAVLDVLEF	YNSKKTSNSQ	KYMSFTDKSA	EDYNSSNALN	VKAVSETPAV	PPVSEDEDDD
190	200	210	220	230	240
DDDATPPPVI	APRPEHTKSV	YTRSVIEPLP	VTPTRDVATS	PISPTENNTT	PPDALTRNTE
250	260	270	280	290	300
KQKKKPKMSD	EEILEKLRSI	VSVGDPKKKY	TRFEKIGQGA	SGTVYTAMDV	ATGQEVAIKQ
310	320	330	340	350	360
MNLQQQPKKE	LIINEILVMR	ENKNPNIVNY	LDSYLVGDEL	WVVMEYLAGG	SLTDVVTETC
370	380	390	400	410	420
MDEGQIAAVC	RECLQALEFL	HSNQVIHRDI	KSDNILLGMD	GSVKLTDFGF	CAQITPEQSK
430	440	450	460	470	480
RSTMVGTPYW	MAPEVVTRKA	YGPKVDIWSL	GIMAIEMIEG	EPPYLNENPL	RALYLIATNG
490	500	510	520	530	540
TPELQNPEKL	SAIFRDFLNR	CLEMDVEKRG	SAKELLQHQF	LKIAKPLSSL	TPLIAAAKEA

TKNNH