Reviewed, UniProtKB/Swiss-Prot Q61097 (KSR1_MOUSE)

Names and origin

Protein names

Recommended name:
    Kinase suppressor of Ras 1
      Short name=mKSR1
Alternative name(s):
    Protein Hb

Gene names

Name:	Ksr1
Synonyms:	Ksr

Organism

Mus musculus (Mouse)

Taxonomic identifier

10090 [NCBI]

Taxonomic lineage

Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Glires › Rodentia › Sciurognathi › Muroidea › Muridae › Murinae › Mus

Protein attributes

Sequence length	873 AA.
Sequence status	Complete.
Sequence processing	The displayed sequence is not processed.
Protein existence	Evidence at protein level.

General annotation (Comments)

Function	Location-regulated scaffolding protein connecting MEK to RAF. Promotes MEK and RAF phosphorylation and activity through assembly of an activated signaling complex. By itself, it has no demonstrated kinase activity.
Subunit structure	Interacts with HSPCA/HSP90, YWHAB/14-3-3, CDC37, MAP2K/MEK, MARK3, PPP2R1A and PPP2CA. Also interacts with RAF and MAPK/ERK, in a Ras-dependent manner. The binding of 14-3-3 proteins to phosphorylated KSR prevents the membrane localization.
Subcellular location	Cytoplasm. Membrane; Peripheral membrane protein. Note= In unstimulated cells, where the phosphorylated form is bound to a 14-3-3 protein, sequestration in the cytoplasm occurs. Following growth factor treatment, the protein is free for membrane translocation, and it moves from the cytoplasm to the cell periphery.
Tissue specificity	Expressed in brain, spleen and testis. Isoform 1 is highly expressed spleen and weakly in testis, and isoform 2 is highly expressed in brain and weakly in testis.
Post-translational modification	Phosphorylated on Ser-297 and, to a higher extent, on Ser-392 by MARK3. Dephosphorylated on Ser-392 by PPP2CA. Phosphorylated KSR is cytoplasmic and dephosphorylated KSR is membrane-associated.
Sequence similarities	Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. Contains 1 phorbol-ester/DAG-type zinc finger. Contains 1 protein kinase domain.

Ontologies

Keywords
Cellular component	Cytoplasm Membrane
Coding sequence diversity	Alternative splicing
Domain	Phorbol-ester binding Zinc-finger
Ligand	Metal-binding Zinc
PTM	Phosphoprotein
Technical term	3D-structure
Gene Ontology (GO)
Molecular function	protein binding Inferred from physical interaction. Source: IntAct
Complete GO annotation...

Binary interactions

With	Entry	#Exp.	IntAct	Notes
NME1	P15531	2	EBI-1536336,EBI-741141	From a different organism.

Alternative products

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

Isoform 1 (identifier: Q61097-1)

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: Q61097-2)

Also known as: B-KSR1;

The sequence of this isoform differs from the canonical sequence as follows:
     474-474: P → PAAYFIHHRQQFIFP
     848-873: DINSSKVMPRFERFGLGTLESGNPKM → EL

Sequence annotation (Features)

Feature key

Position(s)

Length

Description

Graphical view

Molecule processing

Chain

1 – 873

873

Kinase suppressor of Ras 1

Regions

Domain

563 – 833

271

Protein kinase

Zinc finger

333 – 377

45

Phorbol-ester/DAG-type

Compositional bias

17 – 21

5

Poly-Gly

Compositional bias

275 – 278

4

Poly-Pro

Compositional bias

429 – 491

63

Ser-rich

Sites

Metal binding

334

1

Zinc 1

Metal binding

346

1

Zinc 2

Metal binding

349

1

Zinc 2

Metal binding

359

1

Zinc 1

Metal binding

362

1

Zinc 1

Metal binding

367

1

Zinc 2

Metal binding

370

1

Zinc 2

Metal binding

377

1

Zinc 1

Amino acid modifications

Modified residue

256

1

Phosphothreonine By similarity

Modified residue

260

1

Phosphothreonine By similarity

Modified residue

297

1

Phosphoserine; by MARK3

Modified residue

320

1

Phosphoserine By similarity

Modified residue

392

1

Phosphoserine; by MARK3

Natural variations

Alternative sequence

474

1

P → PAAYFIHHRQQFIFP in isoform 2.

Alternative sequence

848 – 873

26

DINSS…GNPKM → EL in isoform 2.

Experimental info

Mutagenesis

297

1

S → A: Constitutive targeting to the plasma membrane; when associated with A-392

Mutagenesis

392

1

S → A: Constitutive targeting to the plasma membrane; when associated with A-297

Mutagenesis

397

1

I → A: Decrease in MARK3 binding; when associated with A-401

Mutagenesis

401

1

V → A: Decrease in MARK3 binding; when associated with A-397

Mutagenesis

572

1

G → E: Decrease in MEK binding

Mutagenesis

589

1

R → M: Almost no MEK binding

Mutagenesis

615

1

R → H: Decrease in MEK binding

Mutagenesis

700

1

D → V: Decrease in MEK binding

Mutagenesis

809

1

C → Y: No MEK binding

Secondary structure

1

.

.

.

.

.

.

.

.

.

.

.

873

Helix Strand Turn

Details...

Beta strand

336 – 339

4

Beta strand

347 – 349

3

Beta strand

356 – 359

4

Turn

360 – 363

4

Beta strand

364 – 369

6

Turn

371 – 373

3

Sequences

	Sequence		Length	Mass (Da)
	Isoform 1 [UniParc]. Last modified November 1, 1996. Version 1. Checksum: EAEEB23FAE715D94	FASTA	873	96,755
	10 20 30 40 50 60 MDRAALRAAA MGEKKEGGGG GAAADGGAGA AVSRALQQCG QLQKLIDISI GSLRGLRTKC 70 80 90 100 110 120 SVSNDLTQQE IRTLEAKLVK YICKQQQSKL SVTPSDRTAE LNSYPRFSDW LYIFNVRPEV 130 140 150 160 170 180 VQEIPQELTL DALLEMDEAK AKEMLRRWGA STEECSRLQQ ALTCLRKVTG LGGEHKMDSG 190 200 210 220 230 240 WSSTDARDSS LGPPMDMLSS LGRAGASTQG PRSISVSALP ASDSPVPGLS EGLSDSCIPL 250 260 270 280 290 300 HTSGRLTPRA LHSFITPPTT PQLRRHAKLK PPRTPPPPSR KVFQLLPSFP TLTRSKSHES 310 320 330 340 350 360 QLGNRIDDVT PMKFELPHGS PQLVRRDIGL SVTHRFSTKS WLSQVCNVCQ KSMIFGVKCK 370 380 390 400 410 420 HCRLKCHNKC TKEAPACRIT FLPLARLRRT ESVPSDINNP VDRAAEPHFG TLPKALTKKE 430 440 450 460 470 480 HPPAMNLDSS SNPSSTTSST PSSPAPFLTS SNPSSATTPP NPSPGQRDSR FSFPDISACS 490 500 510 520 530 540 QAAPLSSTAD STRLDDQPKT DVLGVHEAEA EEPEAGKSEA EDDEEDEVDD LPSSRRPWRG 550 560 570 580 590 600 PISRKASQTS VYLQEWDIPF EQVELGEPIG QGRWGRVHRG RWHGEVAIRL LEMDGHNQDH 610 620 630 640 650 660 LKLFKKEVMN YRQTRHENVV LFMGACMNPP HLAIITSFCK GRTLHSFVRD PKTSLDINKT 670 680 690 700 710 720 RQIAQEIIKG MGYLHAKGIV HKDLKSKNVF YDNGKVVITD FGLFGISGVV REERRENQLK 730 740 750 760 770 780 LSHDWLCYLA PEIVREMIPG RDEDQLPFSK AADVYAFGTV WYELQARDWP FKHQPAEALI 790 800 810 820 830 840 WQIGSGEGVR RVLASVSLGK EVGEILSACW AFDLQERPSF SLLMDMLERL PKLNRRLSHP 850 860 870 GHFWKSADIN SSKVMPRFER FGLGTLESGN PKM
	Isoform 2 (B-KSR1) [UniParc]. Checksum: CAC9B367C41314FA		863	95,861
	10 20 30 40 50 60 MDRAALRAAA MGEKKEGGGG GAAADGGAGA AVSRALQQCG QLQKLIDISI GSLRGLRTKC 70 80 90 100 110 120 SVSNDLTQQE IRTLEAKLVK YICKQQQSKL SVTPSDRTAE LNSYPRFSDW LYIFNVRPEV 130 140 150 160 170 180 VQEIPQELTL DALLEMDEAK AKEMLRRWGA STEECSRLQQ ALTCLRKVTG LGGEHKMDSG 190 200 210 220 230 240 WSSTDARDSS LGPPMDMLSS LGRAGASTQG PRSISVSALP ASDSPVPGLS EGLSDSCIPL 250 260 270 280 290 300 HTSGRLTPRA LHSFITPPTT PQLRRHAKLK PPRTPPPPSR KVFQLLPSFP TLTRSKSHES 310 320 330 340 350 360 QLGNRIDDVT PMKFELPHGS PQLVRRDIGL SVTHRFSTKS WLSQVCNVCQ KSMIFGVKCK 370 380 390 400 410 420 HCRLKCHNKC TKEAPACRIT FLPLARLRRT ESVPSDINNP VDRAAEPHFG TLPKALTKKE 430 440 450 460 470 480 HPPAMNLDSS SNPSSTTSST PSSPAPFLTS SNPSSATTPP NPSPGQRDSR FSFPAAYFIH 490 500 510 520 530 540 HRQQFIFPDI SACSQAAPLS STADSTRLDD QPKTDVLGVH EAEAEEPEAG KSEAEDDEED 550 560 570 580 590 600 EVDDLPSSRR PWRGPISRKA SQTSVYLQEW DIPFEQVELG EPIGQGRWGR VHRGRWHGEV 610 620 630 640 650 660 AIRLLEMDGH NQDHLKLFKK EVMNYRQTRH ENVVLFMGAC MNPPHLAIIT SFCKGRTLHS 670 680 690 700 710 720 FVRDPKTSLD INKTRQIAQE IIKGMGYLHA KGIVHKDLKS KNVFYDNGKV VITDFGLFGI 730 740 750 760 770 780 SGVVREERRE NQLKLSHDWL CYLAPEIVRE MIPGRDEDQL PFSKAADVYA FGTVWYELQA 790 800 810 820 830 840 RDWPFKHQPA EALIWQIGSG EGVRRVLASV SLGKEVGEIL SACWAFDLQE RPSFSLLMDM 850 860 LERLPKLNRR LSHPGHFWKS AEL

References

	« Hide 'large scale' referencesShow 'large scale' references »
[1]	"KSR, a novel protein kinase required for RAS signal transduction." Therrien M., Chang H.C., Solomon N.M., Karim F.D., Wassarman D.A., Rubin G.M. Cell 83:879-888(1995) [PubMed: 8521512] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), INTERACTION WITH HSPCA; YWHAB; CDC37 AND MAP2K.
[2]	"Identification of B-KSR1, a novel brain-specific isoform of KSR1 that functions in neuronal signaling." Mueller J., Cacace A.M., Lyons W.E., McGill C.B., Morrison D.K. Mol. Cell. Biol. 20:5529-5539(2000) [PubMed: 10891492] [Abstract] Cited for: NUCLEOTIDE SEQUENCE (ISOFORMS 1 AND 2), INTERACTION WITH MAPK, MUTAGENESIS OF GLY-572; ARG-589; ARG-615; ASP-700 AND CYS-809, TISSUE SPECIFICITY. Tissue: Brain.
[3]	Pelan S. Submitted (NOV-2004) to the EMBL/GenBank/DDBJ databases Cited for: NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
[4]	"YAC/P1 contigs defining the location of 56 microsatellite markers and several genes across a 3.4cM interval on mouse chromosome 11." Nehls M., Luno K., Schorpp M., Pfeifer D., Krause S., Matysiak-Scholze U., Dierbach H., Boehm T. Mamm. Genome 6:321-331(1995) [PubMed: 7626882] [Abstract] Cited for: NUCLEOTIDE SEQUENCE [MRNA] OF 49-474 (ISOFORMS 1/2). Strain: BALB/c.
[5]	"C-TAK1 regulates Ras signaling by phosphorylating the MAPK scaffold, KSR1." Mueller J., Ory S., Copeland T., Piwnica-Worms H., Morrison D.K. Mol. Cell 8:983-993(2001) [PubMed: 11741534] [Abstract] Cited for: INTERACTION WITH MARK3, PHOSPHORYLATION AT SER-297 AND SER-392, MUTAGENESIS OF SER-297; SER-392; ILE-397 AND VAL-401.
[6]	"Protein phosphatase 2A positively regulates Ras signaling by dephosphorylating KSR1 and Raf-1 on critical 14-3-3 binding sites." Ory S., Zhou M., Conrads T.P., Veenstra T.D., Morrison D.K. Curr. Biol. 13:1356-1364(2003) [PubMed: 12932319] [Abstract] Cited for: INTERACTION WITH PPP2R1A AND PPP2CA, DEPHOSPHORYLATION BY PPP2CA.
[7]	"MAP kinase module: the Ksr connection." Roy F., Therrien M. Curr. Biol. 12:R325-R327(2002) [PubMed: 12007434] [Abstract] Cited for: REVIEW.
[8]	"Solution structure and functional analysis of the cysteine-rich C1 domain of kinase suppressor of Ras (KSR)." Zhou M., Horita D.A., Waugh D.S., Byrd R.A., Morrison D.K. J. Mol. Biol. 315:435-446(2002) [PubMed: 11786023] [Abstract] Cited for: STRUCTURE BY NMR OF 331-378 IN COMPLEX WITH ZINC.
+	Additional computationally mapped references.

Cross-references

Sequence databases

EMBLGenBankDDBJ

U43585 mRNA. Translation: AAC52382.1.
AL592551 Genomic DNA. Translation: CAI24047.1.
X81634 mRNA. Translation: CAA57288.1.

PIR

I48379.

RefSeq

NP_038599.1.

UniGene

Mm.4745

3D structure databases

PDBMSD

Entry	Method	Resolution (Å)	Chain	Positions	PDBsum
1KBE	NMR	-	A	331-378	[»]
1KBF	NMR	-	A	331-378	[»]

ModBase

Search...

Protein-protein interaction databases

IntAct

Q61097.

PTM databases

PhosphoSite

Q61097.

Genome annotation databases

Ensembl

ENSMUSG00000018334. Mus musculus. [Contig view]

GeneID

16706.

KEGG

mmu:16706.

Organism-specific databases

MGI

MGI:105051. Ksr1.

Phylogenomic databases

HOGENOM

Q61097.

HOVERGEN

Q61097.

Gene expression databases

ArrayExpress

Q61097.

CleanEx

MM_KSR1.

GermOnline

ENSMUSG00000018334. Mus musculus.

Family and domain databases

InterPro

IPR002219. DAG_PE_bd.
IPR000719. Prot_kinase_core.
IPR008271. Ser_thr_pkin_AS.
IPR001245. Tyr_pkinase.
[Graphical view]

Pfam

PF00130. C1_1. 1 hit.
PF07714. Pkinase_Tyr. 1 hit.
[Graphical view]

ProDom

PD000001. Prot_kinase. 1 hit.
[Graphical view] [Entries sharing at least one domain]

SMART

SM00109. C1. 1 hit.
[Graphical view]

PROSITE

PS50011. PROTEIN_KINASE_DOM. 1 hit.
PS00108. PROTEIN_KINASE_ST. 1 hit.
PS00479. ZF_DAG_PE_1. 1 hit.
PS50081. ZF_DAG_PE_2. 1 hit.
[Graphical view]

BLOCKS

Search...

Other Resources

SOURCE

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ProtoNet

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Entry information

Entry name

KSR1_MOUSE

Accession

Primary (citable) accession number: Q61097
Secondary accession number(s): Q61648, Q78DX8

Entry history

Integrated into UniProtKB/Swiss-Prot:	December 21, 2004
Last sequence update:	November 1, 1996
Last modified:	July 22, 2008
This is version 67 of the entry and version 1 of the sequence. [Complete history]

Entry status

Reviewed (UniProtKB/Swiss-Prot)

Annotation project

HPI (Human Proteome Initiative)