Q8NB16 (MLKL_HUMAN) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Mixed lineage kinase domain-like protein

Gene names

Name:

MLKL

Organism

Homo sapiens (Human) [Reference proteome]

Taxonomic identifier

9606 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Primates › Haplorrhini › Simiiformes › Catarrhini › Hominoidea › Hominidae › Homininae › Homo

Protein attributes

Sequence length	471 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Required for the execution of programmed necrosis. Ref.10
Subunit structure	Upon TNF-induced necrosis, forms in complex with PGAM5, RIPK1 and RIPK3. Within this complex, may play a role in the proper targeting of RIPK1/RIPK3 to its downstream effector PGAM5. Ref.10
Domain	The protein kinase domain is predicted to be catalytically inactive.
Sequence similarities	Belongs to the protein kinase superfamily. Contains 1 protein kinase domain.

Ontologies

Keywords
Biological process	Necrosis
Coding sequence diversity	Alternative splicing Polymorphism
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Molecular_function	ATP binding Inferred from electronic annotation. Source: InterPro protein kinase activity Inferred from electronic annotation. Source: InterPro
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
RIPK3	Q9Y572	10	EBI-1055040,EBI-298250

Alternative products

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

Isoform 1 Ref.1 Ref.2 (identifier: Q8NB16-1)

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 Ref.4 (identifier: Q8NB16-2)

The sequence of this isoform differs from the canonical sequence as follows:
     179-205: YLPPKCMQEIPQEQIKEIKKEQLSGSP → SLESSSGKSPLEISRFKVKNVKTGSAS
     206-413: Missing.

Note: No experimental confirmation available.

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 471	471	Mixed lineage kinase domain-like protein		PRO_0000248239
Regions
	Domain	194 – 469	276	Protein kinase
Amino acid modifications
	Modified residue	125	1	Phosphoserine Ref.5 Ref.6
Natural variations
	Alternative sequence	179 – 205	27	YLPPK…LSGSP → SLESSSGKSPLEISRFKVKN VKTGSAS in isoform 2. Ref.4		VSP_052133
	Alternative sequence	206 – 413	208	Missing in isoform 2. Ref.4		VSP_052134
	Natural variant	52	1	S → T. Ref.11 Corresponds to variant rs34251827 [ dbSNP | Ensembl ].		VAR_041350
	Natural variant	100	1	D → E. Ref.11 Corresponds to variant rs33987771 [ dbSNP | Ensembl ].		VAR_041351
	Natural variant	132	1	S → P. Ref.11 Corresponds to variant rs35589326 [ dbSNP | Ensembl ].		VAR_041352
	Natural variant	146	1	R → Q. Ref.11 Corresponds to variant rs34515646 [ dbSNP | Ensembl ].		VAR_041353
	Natural variant	169	1	M → L. Ref.11 Corresponds to variant rs55929310 [ dbSNP | Ensembl ].		VAR_041354
	Natural variant	291	1	L → P in a gastric adenocarcinoma sample; somatic mutation. Ref.11		VAR_041355
	Natural variant	364	1	T → M. Ref.11 Corresponds to variant rs34389205 [ dbSNP | Ensembl ].		VAR_041356
	Natural variant	398	1	F → I in a gastric adenocarcinoma sample; somatic mutation. Ref.11		VAR_041357
	Natural variant	421	1	R → H. Ref.11 Corresponds to variant rs55987292 [ dbSNP | Ensembl ].		VAR_041358

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified October 1, 2002. Version 1. Checksum: 005E7F7AB6D20649	FASTA	471	54,479
	10 20 30 40 50 60 MENLKHIITL GQVIHKRCEE MKYCKKQCRR LGHRVLGLIK PLEMLQDQGK RSVPSEKLTT 70 80 90 100 110 120 AMNRFKAALE EANGEIEKFS NRSNICRFLT ASQDKILFKD VNRKLSDVWK ELSLLLQVEQ 130 140 150 160 170 180 RMPVSPISQG ASWAQEDQQD ADEDRRAFQM LRRDNEKIEA SLRRLEINMK EIKETLRQYL 190 200 210 220 230 240 PPKCMQEIPQ EQIKEIKKEQ LSGSPWILLR ENEVSTLYKG EYHRAPVAIK VFKKLQAGSI 250 260 270 280 290 300 AIVRQTFNKE IKTMKKFESP NILRIFGICI DETVTPPQFS IVMEYCELGT LRELLDREKD 310 320 330 340 350 360 LTLGKRMVLV LGAARGLYRL HHSEAPELHG KIRSSNFLVT QGYQVKLAGF ELRKTQTSMS 370 380 390 400 410 420 LGTTREKTDR VKSTAYLSPQ ELEDVFYQYD VKSEIYSFGI VLWEIATGDI PFQGCNSEKI 430 440 450 460 470 RKLVAVKRQQ EPLGEDCPSE LREIIDECRA HDPSVRPSVD EILKKLSTFS K
	Isoform 2 [UniParc]. Checksum: 183FD0023D8A1EC3	FASTA	263	30,279
	10 20 30 40 50 60 MENLKHIITL GQVIHKRCEE MKYCKKQCRR LGHRVLGLIK PLEMLQDQGK RSVPSEKLTT 70 80 90 100 110 120 AMNRFKAALE EANGEIEKFS NRSNICRFLT ASQDKILFKD VNRKLSDVWK ELSLLLQVEQ 130 140 150 160 170 180 RMPVSPISQG ASWAQEDQQD ADEDRRAFQM LRRDNEKIEA SLRRLEINMK EIKETLRQSL 190 200 210 220 230 240 ESSSGKSPLE ISRFKVKNVK TGSASGCNSE KIRKLVAVKR QQEPLGEDCP SELREIIDEC 250 260 RAHDPSVRPS VDEILKKLST FSK

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"The protein kinase complement of the human genome." Manning G., Whyte D.B., Martinez R., Hunter T., Sudarsanam S. Science 298:1912-1934(2002) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), NOMENCLATURE.
[2]	"Complete sequencing and characterization of 21,243 full-length human cDNAs." Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R., Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H., Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S. , Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K., Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H., Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M., Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K., Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T., Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M., Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S., Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H., Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K., Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N., Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S., Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O., Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H., Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B., Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y., Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K., Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T., Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T., Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y., Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H., Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y., Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H., Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O., Isogai T., Sugano S. Nat. Genet. 36:40-45(2004) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1). Tissue: Chondrocyte.
[3]	"The sequence and analysis of duplication-rich human chromosome 16." Martin J., Han C., Gordon L.A., Terry A., Prabhakar S., She X., Xie G., Hellsten U., Chan Y.M., Altherr M., Couronne O., Aerts A., Bajorek E., Black S., Blumer H., Branscomb E., Brown N.C., Bruno W.J. , Buckingham J.M., Callen D.F., Campbell C.S., Campbell M.L., Campbell E.W., Caoile C., Challacombe J.F., Chasteen L.A., Chertkov O., Chi H.C., Christensen M., Clark L.M., Cohn J.D., Denys M., Detter J.C., Dickson M., Dimitrijevic-Bussod M., Escobar J., Fawcett J.J., Flowers D., Fotopulos D., Glavina T., Gomez M., Gonzales E., Goodstein D., Goodwin L.A., Grady D.L., Grigoriev I., Groza M., Hammon N., Hawkins T., Haydu L., Hildebrand C.E., Huang W., Israni S., Jett J., Jewett P.B., Kadner K., Kimball H., Kobayashi A., Krawczyk M.-C., Leyba T., Longmire J.L., Lopez F., Lou Y., Lowry S., Ludeman T., Manohar C.F., Mark G.A., McMurray K.L., Meincke L.J., Morgan J., Moyzis R.K., Mundt M.O., Munk A.C., Nandkeshwar R.D., Pitluck S., Pollard M., Predki P., Parson-Quintana B., Ramirez L., Rash S., Retterer J., Ricke D.O., Robinson D.L., Rodriguez A., Salamov A., Saunders E.H., Scott D., Shough T., Stallings R.L., Stalvey M., Sutherland R.D., Tapia R., Tesmer J.G., Thayer N., Thompson L.S., Tice H., Torney D.C., Tran-Gyamfi M., Tsai M., Ulanovsky L.E., Ustaszewska A., Vo N., White P.S., Williams A.L., Wills P.L., Wu J.-R., Wu K., Yang J., DeJong P., Bruce D., Doggett N.A., Deaven L., Schmutz J., Grimwood J., Richardson P., Rokhsar D.S., Eichler E.E., Gilna P., Lucas S.M., Myers R.M., Rubin E.M., Pennacchio L.A. Nature 432:988-994(2004) [PubMed] [Europe PMC] [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] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). Tissue: Leukocyte.
[5]	"Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle." Daub H., Olsen J.V., Bairlein M., Gnad F., Oppermann F.S., Korner R., Greff Z., Keri G., Stemmann O., Mann M. Mol. Cell 31:438-448(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[6]	"A quantitative atlas of mitotic phosphorylation." Dephoure N., Zhou C., Villen J., Beausoleil S.A., Bakalarski C.E., Elledge S.J., Gygi S.P. Proc. Natl. Acad. Sci. U.S.A. 105:10762-10767(2008) [PubMed] [Europe PMC] [Abstract] Cited for: PHOSPHORYLATION [LARGE SCALE ANALYSIS] AT SER-125, MASS SPECTROMETRY. Tissue: Cervix carcinoma.
[7]	"Quantitative phosphoproteomic analysis of T cell receptor signaling reveals system-wide modulation of protein-protein interactions." Mayya V., Lundgren D.H., Hwang S.-I., Rezaul K., Wu L., Eng J.K., Rodionov V., Han D.K. Sci. Signal. 2:RA46-RA46(2009) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Leukemic T-cell.
[8]	"Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis." Olsen J.V., Vermeulen M., Santamaria A., Kumar C., Miller M.L., Jensen L.J., Gnad F., Cox J., Jensen T.S., Nigg E.A., Brunak S., Mann M. Sci. Signal. 3:RA3-RA3(2010) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. Tissue: Cervix carcinoma.
[9]	"Initial characterization of the human central proteome." Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., Bennett K.L., Superti-Furga G., Colinge J. BMC Syst. Biol. 5:17-17(2011) [PubMed] [Europe PMC] [Abstract] Cited for: IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS].
[10]	"The mitochondrial phosphatase PGAM5 functions at the convergence point of multiple necrotic death pathways." Wang Z., Jiang H., Chen S., Du F., Wang X. Cell 148:228-243(2012) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, IDENTIFICATION IN COMPLEX WITH PGAM5; RIPK1 AND RIPK3.
[11]	"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] [Europe PMC] [Abstract] Cited for: VARIANTS [LARGE SCALE ANALYSIS] THR-52; GLU-100; PRO-132; GLN-146; LEU-169; PRO-291; MET-364; ILE-398 AND HIS-421.
+	Additional computationally mapped references.

Cross-references

Sequence databases
EMBL GenBank DDBJ	AK091708 mRNA. Translation: BAC03728.1. AC109599 Genomic DNA. No translation available. BC028141 mRNA. Translation: AAH28141.1.
IPI	IPI00180781. IPI00182167.
RefSeq	NP_001135969.1. NM_001142497.1. NP_689862.1. NM_152649.2.
UniGene	Hs.119878.
3D structure databases
ProteinModelPortal	Q8NB16.
SMR	Q8NB16. Positions 160-469.
ModBase	Search...
Protein-protein interaction databases
IntAct	Q8NB16. 6 interactions.
MINT	MINT-1033261.
STRING	9606.ENSP00000308351.
PTM databases
PhosphoSite	Q8NB16.
Polymorphism databases
DMDM	74762545.
Proteomic databases
PaxDb	Q8NB16.
PRIDE	Q8NB16.
Protocols and materials databases
DNASU	197259.
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
Ensembl	ENST00000306247; ENSP00000303118; ENSG00000168404. ENST00000308807; ENSP00000308351; ENSG00000168404.
GeneID	197259.
KEGG	hsa:197259.
UCSC	uc002fdb.2. human. uc002fdc.2. human.
Organism-specific databases
CTD	197259.
GeneCards	GC16M074705.
HGNC	HGNC:26617. MLKL.
HPA	HPA010535.
neXtProt	NX_Q8NB16.
PharmGKB	PA142671349.
GenAtlas	Search...
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000113601.
HOVERGEN	HBG056156.
InParanoid	Q8NB16.
KO	K08849.
OMA	SIVMEYC.
Gene expression databases
ArrayExpress	Q8NB16.
Bgee	Q8NB16.
CleanEx	HS_MLKL.
Genevestigator	Q8NB16.
GermOnline	ENSG00000168404. Homo sapiens.
Family and domain databases
InterPro	IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR001245. Ser-Thr/Tyr_kinase_cat_dom. [Graphical view]
Pfam	PF07714. Pkinase_Tyr. 1 hit. [Graphical view]
SUPFAM	SSF56112. Kinase_like. 1 hit.
PROSITE	PS50011. PROTEIN_KINASE_DOM. 1 hit. [Graphical view]
ProtoNet	Search...
Other
ChEMBL	CHEMBL1938217.
ChiTaRS	MLKL. human.
GenomeRNAi	197259.
NextBio	89630.

Entry information

Entry name

MLKL_HUMAN

Accession

Primary (citable) accession number: Q8NB16
Secondary accession number(s): A6NCE4, Q8N6V0

Entry history

Integrated into UniProtKB/Swiss-Prot:	September 5, 2006
Last sequence update:	October 1, 2002
Last modified:	May 1, 2013
This is version 93 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program

Disclaimer

Any medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.