O08678 (MARK1_RAT) Reviewed, UniProtKB/Swiss-Prot

Names and origin

Protein names

Recommended name:
Serine/threonine-protein kinase MARK1
EC=2.7.11.1
EC=2.7.11.26

Alternative name(s):
MAP/microtubule affinity-regulating kinase 1

Gene names

Name:

Mark1

Organism

Rattus norvegicus (Rat) [Reference proteome]

Taxonomic identifier

10116 [NCBI]

Taxonomic lineage

cellular organisms › Eukaryota › Opisthokonta › Metazoa › Eumetazoa › Bilateria › Deuterostomia › Chordata › Craniata › Vertebrata › Gnathostomata › Teleostomi › Euteleostomi › Sarcopterygii › Tetrapoda › Amniota › Mammalia › Theria › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Rattus

Protein attributes

Sequence length	793 AA.
Sequence status	Complete.
Protein existence	Evidence at protein level

General annotation (Comments)

Function	Serine/threonine-protein kinase involved in cell polarity and microtubule dynamics regulation. Phosphorylates DCX, MAP2, MAP4 and MAPT/TAU. Involved in cell polarity by phosphorylating the microtubule-associated proteins MAP2, MAP4 and MAPT/TAU at KXGS motifs, causing detachment from microtubules, and their disassembly. Involved in the regulation of neuronal migration through its dual activities in regulating cellular polarity and microtubule dynamics, possibly by phosphorylating and regulating DCX. Also acts as a positive regulator of the Wnt signaling pathway, probably by mediating phosphorylation of dishevelled proteins (DVL1, DVL2 and/or DVL3). Ref.1 Ref.2 Ref.3
Catalytic activity	ATP + a protein = ADP + a phosphoprotein. Ref.1 ATP + [tau protein] = ADP + [tau protein] phosphate.
Cofactor	Magnesium By similarity. Ref.1
Enzyme regulation	Activated by phosphorylation on Thr-215. Inhibited by phosphorylation at Ser-219. Ref.2
Subcellular location	Cell membrane; Peripheral membrane protein By similarity. Cytoplasm › cytoskeleton. Note: Appears to localize to an intracellular network. Ref.1
Tissue specificity	Highly expressed in brain and spleen and at lower levels in kidney and skeletal muscle. Ref.1
Domain	The UBA domain does not seem to bind ubiquitin and ubiquitin-like and might play a role in regulating the enzyme conformation and localization. Activation of the kinase activity following phosphorylation at Thr-208 is accompanied by a conformational change that alters the orientation of the UBA domain with respect to the catalytic domain By similarity. The KA1 domain mediates binding to phospholipids and targeting to membranes. Binds phosphatidic acid (PA), phosphatidylserine (PtdSer) and phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) By similarity.
Post-translational modification	Phosphorylation at Thr-613 by PRKCZ/aPKC in polarized epithelial cells inhibits the kinase activity By similarity. Phosphorylated at Thr-215 by STK11/LKB1 in complex with STE20-related adapter-alpha (STRADA) pseudo kinase and CAB39. Phosphorylation at Thr-215 by TAOK1 activates the kinase activity, leading to phosphorylation and detachment of MAPT/TAU from microtubules. Phosphorylation at Ser-219 by GSK3-beta (GSK3B) inhibits the kinase activity. Ref.1 Ref.2
Sequence similarities	Belongs to the protein kinase superfamily. CAMK Ser/Thr protein kinase family. SNF1 subfamily. Contains 1 KA1 (kinase-associated) domain. Contains 1 protein kinase domain. Contains 1 UBA domain.

Ontologies

Keywords
Biological process	Wnt signaling pathway
Cellular component	Cell membrane Cytoplasm Cytoskeleton Membrane
Ligand	ATP-binding Lipid-binding Magnesium Metal-binding Nucleotide-binding
Molecular function	Kinase Serine/threonine-protein kinase Transferase
PTM	Phosphoprotein
Technical term	Complete proteome Reference proteome
Gene Ontology (GO)
Biological_process	Wnt receptor signaling pathway Inferred from electronic annotation. Source: UniProtKB-KW intracellular protein kinase cascade Inferred from direct assay Ref.1. Source: UniProtKB microtubule cytoskeleton organization Inferred from direct assay Ref.1. Source: RGD neuron migration Inferred from direct assay Ref.3. Source: UniProtKB
Cellular_component	cytoplasm Inferred from direct assay Ref.1. Source: UniProtKB microtubule cytoskeleton Non-traceable author statement Ref.1. Source: RGD plasma membrane Inferred from sequence or structural similarity. Source: UniProtKB
Molecular_function	ATP binding Inferred from direct assay Ref.1. Source: UniProtKB magnesium ion binding Inferred from direct assay Ref.1. Source: UniProtKB phosphatidic acid binding Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylinositol-4,5-bisphosphate binding Inferred from sequence or structural similarity. Source: UniProtKB phosphatidylserine binding Inferred from sequence or structural similarity. Source: UniProtKB protein serine/threonine kinase activity Inferred from direct assay Ref.3Ref.1. Source: UniProtKB tau-protein kinase activity Inferred from direct assay Ref.1. Source: UniProtKB
Complete GO annotation...

Sequence annotation (Features)

	Feature key	Position(s)	Length	Description	Graphical view	Feature identifier
Molecule processing
	Chain	1 – 793	793	Serine/threonine-protein kinase MARK1		PRO_0000086300
Regions
	Domain	60 – 311	252	Protein kinase
	Domain	329 – 370	42	UBA
	Domain	744 – 793	50	KA1
	Nucleotide binding	66 – 74	9	ATP By similarity UniProtKB Q9H0K1
Sites
	Active site	182	1	Proton acceptor By similarity UniProtKB Q9H0K1
	Binding site	89	1	ATP Ref.1
Amino acid modifications
	Modified residue	5	1	Phosphothreonine By similarity
	Modified residue	215	1	Phosphothreonine; by LKB1 and TAOK1 Ref.1 Ref.2
	Modified residue	219	1	Phosphoserine; by GSK3-beta Ref.1 Ref.2
	Modified residue	394	1	Phosphoserine By similarity
	Modified residue	403	1	Phosphoserine By similarity
	Modified residue	588	1	Phosphoserine By similarity
	Modified residue	613	1	Phosphothreonine; by PKC/PRKCZ By similarity
	Modified residue	666	1	Phosphoserine By similarity
Experimental info
	Mutagenesis	89	1	K → R: Loss of kinase activity. Ref.1
	Mutagenesis	215	1	T → A: Abolishes activation of serine/threonine-protein kinase activity and only basal activity remains. Ref.1 Ref.2
	Mutagenesis	215	1	T → A: Loss of kinase activity. Ref.1 Ref.2
	Mutagenesis	215	1	T → E: Induces an increase of the basal serine/threonine-protein kinase activity. Ref.1 Ref.2
	Mutagenesis	219	1	S → A or E: Loss of activity. Ref.1 Ref.2
	Mutagenesis	219	1	S → A: Loss of kinase activity. Ref.1 Ref.2

Sequences

	Sequence		Length	Mass (Da)
	O08678 [UniParc]. Last modified July 1, 1997. Version 1. Checksum: C5BCCACE0BB9A0A3	FASTA	793	88,235
	10 20 30 40 50 60 MSARTPLPTV NERDTENHTS VDGYTETHIP PTKSSSRQNI PRCRNSITSA TDEQPHIGNY 70 80 90 100 110 120 RLQKTIGKGN FAKVKLARHV LTGREVAVKI IDKTQLNPTS LQKLFREVRI MKILNHPNIV 130 140 150 160 170 180 KLFEVIETEK TLYLVMEYAS GGEVFDYLVA HGRMKEKEAR AKFRQIVSAV QYCHQKCIVH 190 200 210 220 230 240 RDLKAENLLL DADMNIKIAD FGFSNEFTVG NKLDTFCGSP PYAAPELFQG KKYDGPEVDV 250 260 270 280 290 300 WSLGVILYTL VSGSLPFDGQ NLKELRERVL RGKYRVPFYM STDCENLLKK LLVLNPIKRG 310 320 330 340 350 360 SLEQIMKDRW MNVGHEEEEL KPYSEPELDL NDAKRIDIMV TMGFARDEIN DALVSQKYDE 370 380 390 400 410 420 VMATYILLGR KPPEFEGGES LSSGNLCQRS RPSSDLNNST LQSPAHLKVQ RSISANQKQR 430 440 450 460 470 480 RFSDHAGPSI PPAVSYTKRP QANSVESEQK EEWDKDTARR LGSTTVGSKS EVTASPLVGP 490 500 510 520 530 540 DRKKSSAGPS NNVYSGGSMT RRNTYVCERS TDRYAALQNG RDSSLTEMSA SSMSSTGSTV 550 560 570 580 590 600 ASAGPSARPR HQKSMSTSGH PIKVTLPTIK DGSEAYRPGT AQRVPAASPS AHSISASTPD 610 620 630 640 650 660 RTRFPRGSSS RSTFHGEQLR ERRSAAYSGP PASPSHDTAA LAHARRGTST GIISKITSKF 670 680 690 700 710 720 VRRDPSEGEA SGRTDTARGS SGEPKDKEEG KEAKPRSLRF TWSMKTTSSM DPNDMVREIR 730 740 750 760 770 780 KVLDANTCDY EQRERFLLFC VHGDARQDSL VQWEMEVCKL PRLSLNGVRF KRISGTSIAF 790 KNIASKIANE LKL

References

[1]	"MARK - a novel family of protein kinases that phosphorylate microtubule-associated proteins and trigger microtubule disruption." Drewes G., Ebneth A., Preuss U., Mandelkow E.-M., Mandelkow E. Cell 89:297-308(1997) [PubMed] [Europe PMC] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA], FUNCTION, TISSUE SPECIFICITY, SUBCELLULAR LOCATION, PHOSPHORYLATION AT THR-215 AND SER-219, MUTAGENESIS OF LYS-89; THR-215 AND SER-219. Strain: Sprague-Dawley. Tissue: Brain.
[2]	"MARKK, a Ste20-like kinase, activates the polarity-inducing kinase MARK/PAR-1." Timm T., Li X.Y., Biernat J., Jiao J., Mandelkow E., Vandekerckhove J., Mandelkow E.M. EMBO J. 22:5090-5101(2003) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION, ENZYME REGULATION, PHOSPHORYLATION AT THR-215 AND SER-219, MUTAGENESIS OF THR-215 AND SER-219.
[3]	"Doublecortin microtubule affinity is regulated by a balance of kinase and phosphatase activity at the leading edge of migrating neurons." Schaar B.T., Kinoshita K., McConnell S.K. Neuron 41:203-213(2004) [PubMed] [Europe PMC] [Abstract] Cited for: FUNCTION IN PHOSPHORYLATION OF DCX.

Cross-references

Sequence databases
EMBL GenBank DDBJ	Z83868 mRNA. Translation: CAB06294.1.
IPI	IPI00194772.
RefSeq	NP_446399.1. NM_053947.1.
UniGene	Rn.21430.
3D structure databases
ProteinModelPortal	O08678.
SMR	O08678. Positions 54-371, 697-793.
ModBase	Search...
PTM databases
PhosphoSite	O08678.
Proteomic databases
PRIDE	O08678.
Protocols and materials databases
StructuralBiologyKnowledgebase	Search...
Genome annotation databases
GeneID	117016.
KEGG	rno:117016.
UCSC	RGD:619882. rat.
Organism-specific databases
CTD	4139.
RGD	619882. Mark1.
Phylogenomic databases
eggNOG	COG0515.
HOGENOM	HOG000233025.
HOVERGEN	HBG052453.
InParanoid	O08678.
KO	K08798.
OrthoDB	EOG4C2H8X.
Gene expression databases
ArrayExpress	O08678.
Genevestigator	O08678.
GermOnline	ENSRNOG00000002339. Rattus norvegicus.
Family and domain databases
InterPro	IPR001772. KA1_dom. IPR011009. Kinase-like_dom. IPR000719. Prot_kinase_cat_dom. IPR017441. Protein_kinase_ATP_BS. IPR002290. Ser/Thr_dual-sp_kinase_dom. IPR008271. Ser/Thr_kinase_AS. IPR000449. UBA/transl_elong_EF1B_N. IPR015940. UBA/transl_elong_EF1B_N_euk. [Graphical view]
Pfam	PF02149. KA1. 1 hit. PF00069. Pkinase. 1 hit. PF00627. UBA. 1 hit. [Graphical view]
SMART	SM00220. S_TKc. 1 hit. SM00165. UBA. 1 hit. [Graphical view]
SUPFAM	SSF103243. Kinase-assoc_KA1. 1 hit. SSF56112. Kinase_like. 1 hit.
PROSITE	PS50032. KA1. 1 hit. PS00107. PROTEIN_KINASE_ATP. 1 hit. PS50011. PROTEIN_KINASE_DOM. 1 hit. PS00108. PROTEIN_KINASE_ST. 1 hit. PS50030. UBA. 1 hit. [Graphical view]
ProtoNet	Search...
Other
NextBio	619755.

Entry information

Entry name

MARK1_RAT

Accession

Primary (citable) accession number: O08678

Entry history

Integrated into UniProtKB/Swiss-Prot:	April 12, 2005
Last sequence update:	July 1, 1997
Last modified:	April 3, 2013
This is version 101 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation program

Chordata Protein Annotation Program