Reviewed, UniProtKB/Swiss-Prot Q13043 (STK4_HUMAN)

Names and origin

Protein names

Recommended name:
    Serine/threonine-protein kinase 4
    EC=2.7.11.1
Alternative name(s):
    STE20-like kinase MST1
      Short name=MST-1
    Mammalian STE20-like protein kinase 1
    Serine/threonine-protein kinase Krs-2

Gene names

Name:	STK4
Synonyms:	MST1

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

General annotation (Comments)

Function	Stress-activated, pro-apoptotic kinase which, following caspase-cleavage, enters the nucleus and induces chromatin condensation followed by internucleosomal DNA fragmentation. Phosphorylates 'Ser-14' of histone H2B during apoptosis. Phosphorylates FOXO3 upon oxidative stress, which results in its nuclear translocation and cell death initiation.
Catalytic activity	ATP + a protein = ADP + a phosphoprotein.
Cofactor	Magnesium.
Enzyme regulation	Inhibited by the C-terminal non-catalytic region. Activated by caspase-cleavage. Full activation also requires homodimerization and autophosphorylation of Thr-183.
Subunit structure	Homodimer; mediated via the coiled-coil region. Interacts with NORE1, which inhibits autoactivation. Interacts with and stabilizes SAV1. Interacts with RASSF1, which leads to enzyme activation. Interacts with FOXO3.
Subcellular location	Cytoplasm. Nucleus. Note= The caspase-cleaved form cycles between the nucleus and cytoplasm.
Tissue specificity	Ubiquitously expressed.
Post-translational modification	Autophosphorylated on serine and threonine residues.
Sequence similarities	Belongs to the protein kinase superfamily. STE Ser/Thr protein kinase family. STE20 subfamily. Contains 1 protein kinase domain. Contains 1 SARAH domain.

Ontologies

Keywords
Biological process	Apoptosis
Cellular component	Cytoplasm Nucleus
Coding sequence diversity	Alternative splicing Polymorphism
Domain	Coiled coil
Ligand	ATP-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Acetylation Phosphoprotein
Technical term	3D-structure Direct protein sequencing
Gene Ontology (GO)
Biological process	cell morphogenesis Inferred from direct assay. Source: MGI peptidyl-serine phosphorylation Ref.12 Inferred from direct assay. Source: UniProtKB positive regulation of apoptosis Ref.10 Inferred from direct assay. Source: UniProtKB protein amino acid autophosphorylation Inferred from direct assay. Source: MGI protein kinase cascade Inferred from direct assay. Source: UniProtKB
Cellular component	cytoplasm Inferred from electronic annotation. Source: UniProtKB-KW nucleus Inferred from electronic annotation. Source: UniProtKB-KW
Molecular function	ATP binding Inferred from direct assay. Source: UniProtKB magnesium ion binding Inferred from direct assay. Source: UniProtKB protein homodimerization activity Inferred from direct assay. Source: MGI protein serine/threonine kinase activity Ref.12 Inferred from direct assay. Source: UniProtKB transcription factor binding Ref.12 Inferred from physical interaction. Source: UniProtKB
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
itself		1	EBI-367376,EBI-367376
RASSF1	Q9NS23-2	1	EBI-367376,EBI-438698
RASSF5	Q8WWW0	1	EBI-367376,EBI-367390
RASSF5	Q8WWW0-2	2	EBI-367376,EBI-960502
SAV1	Q9H4B6	2	EBI-367376,EBI-1017775

Alternative products

This entry describes 2 isoforms produced by alternative splicing. [Align] [Select]

Isoform 1 (identifier: Q13043-1)

This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

Isoform 2 (identifier: Q13043-2)

The sequence of this isoform differs from the canonical sequence as follows:
     436-462: LKSWTVEDLQKRLLALDPMMEQEIEEI → KTSQEQQSGKDICIQNCQGNLLCRYAF
     463-487: Missing.

Notes: No experimental confirmation available.

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Feature identifier

Molecule processing

Chain

1 – 487

487

Serine/threonine-protein kinase 4

PRO_0000086691

Regions

Domain

30 – 281

252

Protein kinase

Domain

433 – 480

48

SARAH

Nucleotide binding

36 – 44

9

ATP By similarity

Coiled coil

290 – 310

21

Potential

Compositional bias

373 – 378

6

Poly-Glu

Sites

Active site

149

1

Proton acceptor By similarity

Binding site

59

1

ATP

Site

326 – 327

2

Cleavage; by caspase-3

Site

349 – 350

2

Cleavage; by caspase-3

Amino acid modifications

Modified residue

1

1

N-acetylmethionine

Modified residue

183

1

Phosphothreonine; by autocatalysis

Modified residue

320

1

Phosphoserine

Modified residue

433

1

Phosphotyrosine

Natural variations

Alternative sequence

436 – 462

27

LKSWT…EIEEI → KTSQEQQSGKDICIQNCQGN LLCRYAF in isoform 2.

VSP_019851

Alternative sequence

463 – 487

25

Missing in isoform 2.

VSP_019852

Natural variant

162

1

H → N

VAR_041123

Natural variant

310

1

R → Q

VAR_041124

Natural variant

312

1

V → M: dbSNP rs17420378.

VAR_027040

Natural variant

355

1

I → T

VAR_041125

Natural variant

416

1

P → L

VAR_041126

Experimental info

Mutagenesis

59

1

K → R: Loss of activity

Mutagenesis

175

1

T → A: No effect on activity

Mutagenesis

177

1

T → A: No effect on activity

Mutagenesis

183

1

T → A: Loss of activity

Mutagenesis

326

1

D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-349

Mutagenesis

349

1

D → N: Resistant to proteolytic cleavage by caspase during apoptosis; when associated with N-326

Mutagenesis

444

1

L → P: Loss of homodimerization, activation, and autophosphorylation

Sequence conflict

222

1

P → R in AAA83254. Ref.1

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

.

487

Helix Strand Turn

Details...

Helix

19 – 22

4

Beta strand

30 – 35

6

Beta strand

43 – 49

7

Turn

50 – 52

3

Beta strand

55 – 62

8

Helix

68 – 78

11

Beta strand

88 – 94

7

Beta strand

97 – 103

7

Helix

110 – 117

8

Helix

123 – 142

20

Helix

152 – 154

3

Beta strand

155 – 157

3

Beta strand

163 – 165

3

Helix

188 – 190

3

Helix

193 – 196

4

Beta strand

197 – 199

3

Helix

205 – 219

15

Turn

223 – 226

4

Helix

229 – 238

10

Helix

247 – 249

3

Helix

252 – 261

10

Turn

266 – 268

3

Helix

272 – 275

4

Helix

279 – 282

4

Helix

287 – 290

4

Helix

291 – 297

7

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified February 21, 2001. Version 2. Checksum: 150758EBC5F77D5C	FASTA	487	55,630
	10 20 30 40 50 60 METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ 70 80 90 100 110 120 VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT 130 140 150 160 170 180 LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK 190 200 210 220 230 240 RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP 250 260 270 280 290 300 PPTFRKPELW SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV 310 320 330 340 350 360 KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT 370 380 390 400 410 420 LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 430 440 450 460 470 480 NSSDWKIPQD GDYEFLKSWT VEDLQKRLLA LDPMMEQEIE EIRQKYQSKR QPILDAIEAK KRRQQNF
	Isoform 2 [UniParc]. Checksum: 9CFFF2D1FBC316E8		462	52,335
	10 20 30 40 50 60 METVQLRNPP RRQLKKLDED SLTKQPEEVF DVLEKLGEGS YGSVYKAIHK ETGQIVAIKQ 70 80 90 100 110 120 VPVESDLQEI IKEISIMQQC DSPHVVKYYG SYFKNTDLWI VMEYCGAGSV SDIIRLRNKT 130 140 150 160 170 180 LTEDEIATIL QSTLKGLEYL HFMRKIHRDI KAGNILLNTE GHAKLADFGV AGQLTDTMAK 190 200 210 220 230 240 RNTVIGTPFW MAPEVIQEIG YNCVADIWSL GITAIEMAEG KPPYADIHPM RAIFMIPTNP 250 260 270 280 290 300 PPTFRKPELW SDNFTDFVKQ CLVKSPEQRA TATQLLQHPF VRSAKGVSIL RDLINEAMDV 310 320 330 340 350 360 KLKRQESQQR EVDQDDEENS EEDEMDSGTM VRAVGDEMGT VRVASTMTDG ANTMIEHDDT 370 380 390 400 410 420 LPSQLGTMVI NAEDEEEEGT MKRRDETMQP AKPSFLEYFE QKEKENQINS FGKSVPGPLK 430 440 450 460 NSSDWKIPQD GDYEFKTSQE QQSGKDICIQ NCQGNLLCRY AF

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"Cloning and characterization of a human protein kinase with homology to Ste20." Creasy C.L., Chernoff J. J. Biol. Chem. 270:21695-21700(1995) [PubMed: 7665586] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), VARIANT MET-312.
[2]	"Newly identified stress-responsive protein kinases, Krs-1 and Krs-2." Taylor L.K., Wang H.C., Erikson R.L. Proc. Natl. Acad. Sci. U.S.A. 93:10099-10104(1996) [PubMed: 8816758] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), FUNCTION.
[3]	"The DNA sequence and comparative analysis of human chromosome 20." Deloukas P., Matthews L.H., Ashurst J.L., Burton J., Gilbert J.G.R., Jones M., Stavrides G., Almeida J.P., Babbage A.K., Bagguley C.L., Bailey J., Barlow K.F., Bates K.N., Beard L.M., Beare D.M., Beasley O.P., Bird C.P., Blakey S.E. , Bridgeman A.M., Brown A.J., Buck D., Burrill W.D., Butler A.P., Carder C., Carter N.P., Chapman J.C., Clamp M., Clark G., Clark L.N., Clark S.Y., Clee C.M., Clegg S., Cobley V.E., Collier R.E., Connor R.E., Corby N.R., Coulson A., Coville G.J., Deadman R., Dhami P.D., Dunn M., Ellington A.G., Frankland J.A., Fraser A., French L., Garner P., Grafham D.V., Griffiths C., Griffiths M.N.D., Gwilliam R., Hall R.E., Hammond S., Harley J.L., Heath P.D., Ho S., Holden J.L., Howden P.J., Huckle E., Hunt A.R., Hunt S.E., Jekosch K., Johnson C.M., Johnson D., Kay M.P., Kimberley A.M., King A., Knights A., Laird G.K., Lawlor S., Lehvaeslaiho M.H., Leversha M.A., Lloyd C., Lloyd D.M., Lovell J.D., Marsh V.L., Martin S.L., McConnachie L.J., McLay K., McMurray A.A., Milne S.A., Mistry D., Moore M.J.F., Mullikin J.C., Nickerson T., Oliver K., Parker A., Patel R., Pearce T.A.V., Peck A.I., Phillimore B.J.C.T., Prathalingam S.R., Plumb R.W., Ramsay H., Rice C.M., Ross M.T., Scott C.E., Sehra H.K., Shownkeen R., Sims S., Skuce C.D., Smith M.L., Soderlund C., Steward C.A., Sulston J.E., Swann R.M., Sycamore N., Taylor R., Tee L., Thomas D.W., Thorpe A., Tracey A., Tromans A.C., Vaudin M., Wall M., Wallis J.M., Whitehead S.L., Whittaker P., Willey D.L., Williams L., Williams S.A., Wilming L., Wray P.W., Hubbard T., Durbin R.M., Bentley D.R., Beck S., Rogers J. Nature 414:865-871(2001) [PubMed: 11780052] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC)." The MGC Project Team Genome Res. 14:2121-2127(2004) [PubMed: 15489334] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA]. Tissue: Bone, Brain and Liver.
[5]	Bienvenut W.V., Matallanas D., Cooper W.N., Kolch W. Submitted (JUL-2007) to UniProtKB Cited for: PROTEIN SEQUENCE OF 1-7; 16-94; 118-144; 152-181; 232-259; 270-282; 292-301; 333-342; 384-402; 405-413; 421-465 AND 470-481, ACETYLATION AT MET-1, MASS SPECTROMETRY. Tissue: Mammary carcinoma.
[6]	"The Ste20-like protein kinase, Mst1, dimerizes and contains an inhibitory domain." Creasy C.L., Ambrose D.M., Chernoff J. J. Biol. Chem. 271:21049-21053(1996) [PubMed: 8702870] [Abstract] Cited for: FUNCTION, HOMODIMERIZATION, ENZYME REGULATION.
[7]	"MST, a physiological caspase substrate, highly sensitizes apoptosis both upstream and downstream of caspase activation." Lee K.-K., Ohyama T., Yajima N., Tsubuki S., Yonehara S. J. Biol. Chem. 276:19276-19285(2001) [PubMed: 11278283] [Abstract] Cited for: SUBCELLULAR LOCATION, FUNCTION, CLEAVAGE BY CASPASE, MUTAGENESIS OF ASP-326 AND ASP-349.
[8]	"Caspase cleavage of MST1 promotes nuclear translocation and chromatin condensation." Ura S., Masuyama N., Graves J.D., Gotoh Y. Proc. Natl. Acad. Sci. U.S.A. 98:10148-10153(2001) [PubMed: 11517310] [Abstract] Cited for: FUNCTION, SUBCELLULAR LOCATION.
[9]	"Apoptotic phosphorylation of histone H2B is mediated by mammalian sterile twenty kinase." Cheung W.L., Ajiro K., Samejima K., <