Reviewed, UniProtKB/Swiss-Prot O76039 (CDKL5_HUMAN)

Names and origin

Protein names

Recommended name:
    Cyclin-dependent kinase-like 5
    EC=2.7.11.22
Alternative name(s):
    Serine/threonine-protein kinase 9

Gene names

Name:	CDKL5
Synonyms:	STK9

Organism

Homo sapiens (Human)

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo

Protein attributes

Sequence length	1030 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Tissue specificity	Expressed in brain, lung, kidney, prostate, ovary, placenta, pancreas and testis.
Involvement in disease	Chromosomal aberrations involving CDKL5 are a cause of X-linked infantile spasm syndrome (ISSX) [MIM:308350]; also known as X-linked West syndrome. Translocation t(X;6)(p22.3;q14); translocation t(X;7)(p22.3;p15). ISSX is characterized by infantile spasms, hypsarrhythmia on EEG, and developmental arrest leading to severe to profound mental retardation. Defects in CDKL5 are a cause of X-linked infantile spasm syndrome (ISSX) [MIM:308350]. Defects in CDKL5 are a cause of atypical CDKL5-related Rett syndrome [MIM:300672]. Rett syndrome is an X-linked dominant disease. It is a progressive neurologic developmental disorder and one of the most common causes of mental retardation in females. Patients appear to develop normally until 6 to 18 months of age, then gradually lose speech and purposeful hand movements and develop microcephaly, seizures, autism, ataxia, intermittent hyperventilation, and stereotypic hand movements. After initial regression, the condition stabilizes and patients usually survive into adulthood. Atypical, CDKL5-related Rett syndrome is characterized by a severe early-onset phenotype and atypical features such as infantile spasms.
Sequence similarities	Belongs to the protein kinase superfamily. CMGC Ser/Thr protein kinase family. CDC2/CDKX subfamily. Contains 1 protein kinase domain.
Caution	It is uncertain whether Met-1 or Met-10 is the initiator.
Sequence caution	The sequence CAA61445.1 differs from that shown. Reason: Frameshift at position 415.

Ontologies

Keywords
Coding sequence diversity	Chromosomal rearrangement Polymorphism
Disease	Disease mutation Mental retardation
Ligand	ATP-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
Gene Ontology (GO)
Biological process	protein amino acid autophosphorylation Inferred from direct assay. Source: HGNC
Cellular component	cytoplasm Inferred from direct assay. Source: HPA nucleus Inferred from direct assay. Source: HGNC
Molecular function	ATP binding Inferred from direct assay. Source: HGNC cyclin-dependent protein kinase activity Inferred from electronic annotation. Source: EC
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
ABL1	P00519	1	EBI-1752465,EBI-375543
FYN	P06241	1	EBI-1752465,EBI-515315
GRB2	P62993	1	EBI-1752465,EBI-401755

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 1030	1030	Cyclin-dependent kinase-like 5		PRO_0000085826
Regions
	Domain	13 – 297	285	Protein kinase
	Nucleotide binding	19 – 27	9	ATP By similarity
	Compositional bias	784 – 789	6	Poly-Lys
Sites
	Active site	135	1	Proton acceptor By similarity
	Binding site	42	1	ATP By similarity
Natural variations
	Natural variant	152	1	C → F in atypical CDKL5-related Rett syndrome.		VAR_023560
	Natural variant	175	1	R → S in atypical CDKL5-related Rett syndrome.		VAR_023561
	Natural variant	180	1	P → L in ISSX.		VAR_037635
	Natural variant	368	1	N → H in a colorectal cancer sample; somatic mutation.		VAR_036578
	Natural variant	374	1	A → T in a metastatic melanoma sample; somatic mutation.		VAR_041997
	Natural variant	574	1	P → Q in an ovarian serous carcinoma sample; somatic mutation.		VAR_041998
	Natural variant	734	1	T → A		VAR_041999
	Natural variant	791	1	Q → P: dbSNP rs35478150.		VAR_023562
	Natural variant	793	1	V → A in ISSX; uncertain pathogenicity.		VAR_037636
	Natural variant	999	1	V → M: dbSNP rs35693326.		VAR_037637
	Natural variant	1023	1	E → G		VAR_042000
Experimental info
	Sequence conflict	339 – 340	2	HR → GT in CAA61445. Ref.4
	Sequence conflict	541	1	L → W in CAA61445. Ref.4
	Sequence conflict	731 – 764	34	Missing in CAA61445. Ref.4

Sequences

	Sequence		Length	Mass (Da)
	O76039-1 [UniParc]. Last modified November 1, 1998. Version 1. Checksum: 8A1C9C438610EF08	FASTA	1,030	115,538
	10 20 30 40 50 60 MKIPNIGNVM NKFEILGVVG EGAYGVVLKC RHKETHEIVA IKKFKDSEEN EEVKETTLRE 70 80 90 100 110 120 LKMLRTLKQE NIVELKEAFR RRGKLYLVFE YVEKNMLELL EEMPNGVPPE KVKSYIYQLI 130 140 150 160 170 180 KAIHWCHKND IVHRDIKPEN LLISHNDVLK LCDFGFARNL SEGNNANYTE YVATRWYRSP 190 200 210 220 230 240 ELLLGAPYGK SVDMWSVGCI LGELSDGQPL FPGESEIDQL FTIQKVLGPL PSEQMKLFYS 250 260 270 280 290 300 NPRFHGLRFP AVNHPQSLER RYLGILNSVL LDLMKNLLKL DPADRYLTEQ CLNHPTFQTQ 310 320 330 340 350 360 RLLDRSPSRS AKRKPYHVES STLSNRNQAG KSTALQSHHR SNSKDIQNLS VGLPRADEGL 370 380 390 400 410 420 PANESFLNGN LAGASLSPLH TKTYQASSQP GSTSKDLTNN NIPHLLSPKE AKSKTEFDFN 430 440 450 460 470 480 IDPKPSEGPG TKYLKSNSRS QQNRHSFMES SQSKAGTLQP NEKQSRHSYI DTIPQSSRSP 490 500 510 520 530 540 SYRTKAKSHG ALSDSKSVSN LSEARAQIAE PSTSRYFPSS CLDLNSPTSP TPTRHSDTRT 550 560 570 580 590 600 LLSPSGRNNR NEGTLDSRRT TTRHSKTMEE LKLPEHMDSS HSHSLSAPHE SFSYGLGYTS 610 620 630 640 650 660 PFSSQQRPHR HSMYVTRDKV RAKGLDGSLS IGQGMAARAN SLQLLSPQPG EQLPPEMTVA 670 680 690 700 710 720 RSSVKETSRE GTSSFHTRQK SEGGVYHDPH SDDGTAPKEN RHLYNDPVPR RVGSFYRVPS 730 740 750 760 770 780 PRPDNSFHEN NVSTRVSSLP SESSSGTNHS KRQPAFDPWK SPENISHSEQ LKEKEKQGFF 790 800 810 820 830 840 RSMKKKKKKS QTVPNSDSPD LLTLQKSIHS ASTPSSRPKE WRPEKISDLQ TQSQPLKSLR 850 860 870 880 890 900 KLLHLSSASN HPASSDPRFQ PLTAQQTKNS FSEIRIHPLS QASGGSSNIR QEPAPKGRPA 910 920 930 940 950 960 LQLPDGGCDG RRQRHHSGPQ DRRFMLRTTE QQGEYFCCGD PKKPHTPCVP NRALHRPISS 970 980 990 1000 1010 1020 PAPYPVLQVR GTSMCPTLQV RGTDAFSCPT QQSGFSFFVR HVMREALIHR AQVNQAALLT 1030 YHENAALTGK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Identification and characterization of a novel serine-threonine kinase gene from the Xp22 region." Montini E., Andolfi G., Caruso A., Buchner G., Walpole S.M., Mariani M., Consalez G.G., Trump D., Ballabio A., Franco B. Genomics 51:427-433(1998) [PubMed: 9721213] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA].
[2]	"Disruption of the serine/threonine kinase 9 gene causes severe X-linked infantile spasms and mental retardation." Kalscheuer V.M., Tao J., Donnelly A., Hollway G., Schwinger E., Kuebart S., Menzel C., Hoeltzenbein M., Tommerup N., Eyre H., Harbord M., Haan E., Sutherland G.R., Ropers H.-H., Gecz J. Am. J. Hum. Genet. 72:1401-1411(2003) [PubMed: 12736870] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], INVOLVEMENT IN X-LINKED INFANTILE SPASM SYNDROME, CHROMOSOMAL TRANSLOCATION, VARIANT PRO-791.
[3]	"The DNA sequence of the human X chromosome." Ross M.T., Grafham D.V., Coffey A.J., Scherer S., McLay K., Muzny D., Platzer M., Howell G.R., Burrows C., Bird C.P., Frankish A., Lovell F.L., Howe K.L., Ashurst J.L., Fulton R.S., Sudbrak R., Wen G., Jones M.C. , Hurles M.E., Andrews T.D., Scott C.E., Searle S., Ramser J., Whittaker A., Deadman R., Carter N.P., Hunt S.E., Chen R., Cree A., Gunaratne P., Havlak P., Hodgson A., Metzker M.L., Richards S., Scott G., Steffen D., Sodergren E., Wheeler D.A., Worley K.C., Ainscough R., Ambrose K.D., Ansari-Lari M.A., Aradhya S., Ashwell R.I., Babbage A.K., Bagguley C.L., Ballabio A., Banerjee R., Barker G.E., Barlow K.F., Barrett I.P., Bates K.N., Beare D.M., Beasley H., Beasley O., Beck A., Bethel G., Blechschmidt K., Brady N., Bray-Allen S., Bridgeman A.M., Brown A.J., Brown M.J., Bonnin D., Bruford E.A., Buhay C., Burch P., Burford D., Burgess J., Burrill W., Burton J., Bye J.M., Carder C., Carrel L., Chako J., Chapman J.C., Chavez D., Chen E., Chen G., Chen Y., Chen Z., Chinault C., Ciccodicola A., Clark S.Y., Clarke G., Clee C.M., Clegg S., Clerc-Blankenburg K., Clifford K., Cobley V., Cole C.G., Conquer J.S., Corby N., Connor R.E., David R., Davies J., Davis C., Davis J., Delgado O., Deshazo D., Dhami P., Ding Y., Dinh H., Dodsworth S., Draper H., Dugan-Rocha S., Dunham A., Dunn M., Durbin K.J., Dutta I., Eades T., Ellwood M., Emery-Cohen A., Errington H., Evans K.L., Faulkner L., Francis F., Frankland J., Fraser A.E., Galgoczy P., Gilbert J., Gill R., Gloeckner G., Gregory S.G., Gribble S., Griffiths C., Grocock R., Gu Y., Gwilliam R., Hamilton C., Hart E.A., Hawes A., Heath P.D., Heitmann K., Hennig S., Hernandez J., Hinzmann B., Ho S., Hoffs M., Howden P.J., Huckle E.J., Hume J., Hunt P.J., Hunt A.R., Isherwood J., Jacob L., Johnson D., Jones S., de Jong P.J., Joseph S.S., Keenan S., Kelly S., Kershaw J.K., Khan Z., Kioschis P., Klages S., Knights A.J., Kosiura A., Kovar-Smith C., Laird G.K., Langford C., Lawlor S., Leversha M., Lewis L., Liu W., Lloyd C., Lloyd D.M., Loulseged H., Loveland J.E., Lovell J.D., Lozado R., Lu J., Lyne R., Ma J., Maheshwari M., Matthews L.H., McDowall J., McLaren S., McMurray A., Meidl P., Meitinger T., Milne S., Miner G., Mistry S.L., Morgan M., Morris S., Mueller I., Mullikin J.C., Nguyen N., Nordsiek G., Nyakatura G., O'dell C.N., Okwuonu G., Palmer S., Pandian R., Parker D., Parrish J., Pasternak S., Patel D., Pearce A.V., Pearson D.M., Pelan S.E., Perez L., Porter K.M., Ramsey Y., Reichwald K., Rhodes S., Ridler K.A., Schlessinger D., Schueler M.G., Sehra H.K., Shaw-Smith C., Shen H., Sheridan E.M., Shownkeen R., Skuce C.D., Smith M.L., Sotheran E.C., Steingruber H.E., Steward C.A., Storey R., Swann R.M., Swarbreck D., Tabor P.E., Taudien S., Taylor T., Teague B., Thomas K., Thorpe A., Timms K., Tracey A., Trevanion S., Tromans A.C., d'Urso M., Verduzco D., Villasana D., Waldron L., Wall M., Wang Q., Warren J., Warry G.L., Wei X., West A., Whitehead S.L., Whiteley M.N., Wilkinson J.E., Willey D.L., Williams G., Williams L., Williamson A., Williamson H., Wilming L., Woodmansey R.L., Wray P.W., Yen J., Zhang J., Zhou J., Zoghbi H., Zorilla S., Buck D., Reinhardt R., Poustka A., Rosenthal A., Lehrach H., Meindl A., Minx P.J., Hillier L.W., Willard H.F., Wilson R.K., Waterston R.H., Rice C.M., Vaudin M., Coulson A., Nelson D.L., Weinstock G., Sulston J.E., Durbin R.M., Hubbard T., Gibbs R.A., Beck S., Rogers J., Bentley D.R. Nature 434:325-337(2005) [PubMed: 15772651] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"Differential screening leads to novel genetic markers of monocyte to macrophage maturation." Krause S.W., Rehli M., Kreutz M., Schwarzfischer L., Paulauskis J.D., Andreesen J.D. J. Leukoc. Biol. 60:540-545(1996) [PubMed: 8864140] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 339-789.
[5]	"Mutations of CDKL5 cause a severe neurodevelopmental disorder with infantile spasms and mental retardation." Weaving L.S., Christodoulou J., Williamson S.L., Friend K.L., McKenzie O.L.D., Archer H., Evans J., Clarke A., Pelka G.J., Tam P.P.L., Watson C., Lahooti H., Ellaway C.J., Bennetts B., Leonard H., Gecz J. Am. J. Hum. Genet. 75:1079-1093(2004) [PubMed: 15492925] [Abstract] Cited for: INVOLVEMENT IN ATYPICAL CDKL5-RELATED RETT SYNDROME.
[6]	"Mutations in the X-linked cyclin-dependent kinase-like 5 (CDKL5/STK9) gene are associated with severe neurodevelopmental retardation." Tao J., Van Esch H., Hagedorn-Greiwe M., Hoffmann K., Moser B., Raynaud M., Sperner J., Fryns J.-P., Schwinger E., Gecz J., Ropers H.-H., Kalscheuer V.M. Am. J. Hum. Genet. 75:1149-1154(2004) [PubMed: 15499549] [Abstract] Cited for: VARIANTS ATYPICAL CDKL5-RELATED RETT SYNDROME PHE-152 AND SER-175, VARIANT PRO-791.
[7]	"CDKL5/STK9 is mutated in Rett syndrome variant with infantile spasms." Scala E., Ariani F., Mari F., Caselli R., Pescucci C., Longo I., Meloni I., Giachino D., Bruttini M., Hayek G., Zappella M., Renieri A. J. Med. Genet. 42:103-107(2005) [PubMed: 15689447] [Abstract] Cited for: INVOLVEMENT IN ATYPICAL RETT SYNDROME.
[8]	"CDKL5 mutations cause infantile spasms, early onset seizures, and severe mental retardation in female patients." Archer H.L., Evans J., Edwards S., Colley J., Newbury-Ecob R., O'Callaghan F., Huyton M., O'Regan M., Tolmie J., Sampson J., Clarke A., Osborne J. J. Med. Genet. 43:729-734(2006) [PubMed: 16611748] [Abstract] Cited for: VARIANTS ISSX LEU-180 AND ALA-793.
[9]	"The consensus coding sequences of human breast and colorectal cancers." Sjoeblom T., Jones S., Wood L.D., Parsons D.W., Lin J., Barber T.D., Mandelker D., Leary R.J., Ptak J., Silliman N., Szabo S., Buckhaults P., Farrell C., Meeh P., Markowitz S.D., Willis J., Dawson D., Willson J.K.V. , Gazdar A.F., Hartigan J., Wu L., Liu C., Parmigiani G., Park B.H., Bachman K.E., Papadopoulos N., Vogelstein B., Kinzler K.W., Velculescu V.E. Science 314:268-274(2006) [PubMed: 16959974] [Abstract] Cited for: VARIANT [LARGE SCALE ANALYSIS] HIS-368.
[10]	"Patterns of somatic mutation in human cancer genomes." Greenman C., Stephens P., Smith R., Dalgliesh G.L., Hunter C., Bignell G., Davies H., Teague J., Butler A., Stevens C., Edkins S., O'Meara S., Vastrik I., Schmidt E.E., Avis T., Barthorpe S., Bhamra G., Buck G. , Choudhury B., Clements J., Cole J., Dicks E., Forbes S., Gray K., Halliday K., Harrison R., Hills K., Hinton J., Jenkinson A., Jones D., Menzies A., Mironenko T., Perry J., Raine K., Richardson D., Shepherd R., Small A., Tofts C., Varian J., Webb T., West S., Widaa S., Yates A., Cahill D.P., Louis D.N., Goldstraw P., Nicholson A.G., Brasseur F., Looijenga L., Weber B.L., Chiew Y.-E., DeFazio A., Greaves M.F., Green A.R., Campbell P., Birney E., Easton D.F., Chenevix-Trench G., Tan M.-H., Khoo S.K., Teh B.T., Yuen S.T., Leung S.Y., Wooster R., Futreal P.A., Stratton M.R. Nature 446:153-158(2007) [PubMed: 17344846] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-374; GLN-574; ALA-734; PRO-791 AND GLY-1023.
+	Additional computationally mapped references.

Web resources

GeneReviews

Cross-references

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Sequence databases
EMBLGenBankDDBJ	Y15057 mRNA. Translation: CAA75342.1. AY217744 mRNA. Translation: AAO64440.1. Z92542, AL109798 Genomic DNA. Translation: CAI42485.1. AL109798, Z92542 Genomic DNA. Translation: CAI41159.1. X89059 mRNA. Translation: CAA61445.1. Frameshift.
PIR	S58296.
RefSeq	NP_001032420.1. NP_003150.1.
UniGene	Hs.659851
3D structure databases
HSSP	HSSP built from PDB template 1H00 based on UniProtKB P24941.
ModBase	Search...
Protein-protein interaction databases
IntAct	O76039.
PTM databases
PhosphoSite	O76039.
Genome annotation databases
Ensembl	ENSG00000008086. Homo sapiens. [Contig view]
GeneID	6792.
KEGG	hsa:6792.
Organism-specific databases
H-InvDB	HIX0021511.
HGNC	HGNC:11411. CDKL5.
HPA	CAB011577. HPA002847.
MIM	300203. gene. 300672. phenotype. 308350. phenotype.
Orphanet	778. Rett syndrome. 3451. West syndrome.
PharmGKB	PA36218.
GenAtlas	Search...
GeneCards	Search...
Phylogenomic databases
HOVERGEN	O76039.
Gene expression databases
ArrayExpress	O76039.
CleanEx	HS_CDKL5.
GermOnline	ENSG00000008086. Homo sapiens.
Family and domain databases
InterPro	IPR000719. Prot_kinase_core. IPR017441. Protein_kinase_ATP_bd_CS. IPR017442. Se/Thr_pkinase-rel. IPR008271. Ser_thr_pkin_AS. IPR002290. Ser_thr_pkinase. [Graphical view]
Pfam	PF00069. Pkinase. 1 hit. [Graphical view]
ProDom	PD000001. Prot_kinase. 1 hit. [Graphical view] [Entries sharing at least one domain]
SMART	SM00220. S_TKc. 1 hit. [Graphical view]
PROSITE	PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. [Graphical view]
ProtoNet	Search...
Other Resources
NextBio	26529.
SOURCE	Search...