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UniProtKB - P04049 (RAF1_HUMAN)

Protein

RAF proto-oncogene serine/threonine-protein kinase

Gene

RAF1

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Serine/threonine-protein kinase that acts as a regulatory link between the membrane-associated Ras GTPases and the MAPK/ERK cascade, and this critical regulatory link functions as a switch determining cell fate decisions including proliferation, differentiation, apoptosis, survival and oncogenic transformation. RAF1 activation initiates a mitogen-activated protein kinase (MAPK) cascade that comprises a sequential phosphorylation of the dual-specific MAPK kinases (MAP2K1/MEK1 and MAP2K2/MEK2) and the extracellular signal-regulated kinases (MAPK3/ERK1 and MAPK1/ERK2). The phosphorylated form of RAF1 (on residues Ser-338 and Ser-339, by PAK1) phosphorylates BAD/Bcl2-antagonist of cell death at 'Ser-75'. Phosphorylates adenylyl cyclases: ADCY2, ADCY5 and ADCY6, resulting in their activation. Phosphorylates PPP1R12A resulting in inhibition of the phosphatase activity. Phosphorylates TNNT2/cardiac muscle troponin T. Can promote NF-kB activation and inhibit signal transducers involved in motility (ROCK2), apoptosis (MAP3K5/ASK1 and STK3/MST2), proliferation and angiogenesis (RB1). Can protect cells from apoptosis also by translocating to the mitochondria where it binds BCL2 and displaces BAD/Bcl2-antagonist of cell death. Regulates Rho signaling and migration, and is required for normal wound healing. Plays a role in the oncogenic transformation of epithelial cells via repression of the TJ protein, occludin (OCLN) by inducing the up-regulation of a transcriptional repressor SNAI2/SLUG, which induces down-regulation of OCLN. Restricts caspase activation in response to selected stimuli, notably Fas stimulation, pathogen-mediated macrophage apoptosis, and erythroid differentiation.8 Publications

Catalytic activityi

ATP + a protein = ADP + a phosphoprotein.

Cofactori

Zn2+Note: Binds 2 Zn2+ ions per subunit.

Activity regulationi

Regulation is a highly complex process involving membrane recruitment, protein-protein interactions, dimerization, and phosphorylation/dephosphorylation events. Ras-GTP recruits RAF1 to the membrane, thereby promoting its activation. The inactive conformation of RAF1 is maintained by autoinhibitory interactions occurring between the N-terminal regulatory and the C-terminal catalytic domains and by the binding of a 14-3-3 protein that contacts two phosphorylation sites, Ser-259 and Ser-621. Upon mitogenic stimulation, Ras and PPP2R1A cooperate to release autoinhibition and the subsequent phosphorylation of activating sites: Ser-338, Tyr-341, Thr-491, and Ser-494, yields a fully active kinase. Through a negative feedback mechanism involving MAPK1/ERK2, RAF1 is phosphorylated on Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2, which yields an inactive, desensitized kinase. The signaling-competent conformation of RAF1 is finally re-established by the coordinated action of PIN1, a prolyl isomerase that converts pSer and pThr residues from the cis to the trans conformation, which is preferentially recognized and dephosphorylated by PPP2R1A. Activated by homodimerization and heterodimerization (with BRAF). Also regulated through association with other proteins such as KSR2, CNKSR1/CNK1, PEBP1/RKIP, PHB/prohibitin and SPRY4. PEBP1/RKIP acts by dissociating RAF1 from its substrates MAP2K1/MEK1 and MAP2K2/MEK2. PHB/prohibitin facilitates the displacement of 14-3-3 from RAF1 by activated Ras, thereby promoting cell membrane localization and phosphorylation of RAF1 at the activating Ser-338. SPRY4 inhibits Ras-independent, but not Ras-dependent, activation of RAF1. CNKSR1/CNK1 regulates Src-mediated RAF1 activation.8 Publications

Sites

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Metal bindingi139Zinc 11
Metal bindingi152Zinc 21
Metal bindingi155Zinc 21
Metal bindingi165Zinc 11
Metal bindingi168Zinc 11
Metal bindingi173Zinc 21
Metal bindingi176Zinc 21
Metal bindingi184Zinc 11
Binding sitei375ATPPROSITE-ProRule annotation1
Active sitei468Proton acceptor1

Regions

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47
Nucleotide bindingi355 – 363ATPPROSITE-ProRule annotation9

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

GO - Biological processi

View the complete GO annotation on QuickGO ...

Keywordsi

Molecular functionKinase, Serine/threonine-protein kinase, Transferase
LigandATP-binding, Metal-binding, Nucleotide-binding, Zinc

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-2672351 Stimuli-sensing channels
R-HSA-392517 Rap1 signalling
R-HSA-430116 GP1b-IX-V activation signalling
R-HSA-442742 CREB phosphorylation through the activation of Ras
R-HSA-5621575 CD209 (DC-SIGN) signaling
R-HSA-5673000 RAF activation
R-HSA-5674135 MAP2K and MAPK activation
R-HSA-5674499 Negative feedback regulation of MAPK pathway
R-HSA-5675221 Negative regulation of MAPK pathway
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802952 Signaling by BRAF and RAF fusions
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF
SignaLinkiP04049
SIGNORiP04049

Protein family/group databases

MoonDBiP04049 Predicted

Names & Taxonomyi

Protein namesi
Recommended name:
RAF proto-oncogene serine/threonine-protein kinase (EC:2.7.11.1)
Alternative name(s):
Proto-oncogene c-RAF
Short name:
cRaf
Raf-1
Gene namesi
Name:RAF1
Synonyms:RAF
OrganismiHomo sapiens (Human)
Taxonomic identifieri9606 [NCBI]
Taxonomic lineageiEukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo
Proteomesi
  • UP000005640 Componenti: Chromosome 3

Organism-specific databases

EuPathDBiHostDB:ENSG00000132155.11
HGNCiHGNC:9829 RAF1
MIMi164760 gene
neXtProtiNX_P04049

Subcellular locationi

Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

Keywords - Cellular componenti

Cell membrane, Cytoplasm, Membrane, Mitochondrion, Nucleus

Pathology & Biotechi

Involvement in diseasei

Noonan syndrome 5 (NS5)3 Publications
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA form of Noonan syndrome, a disease characterized by short stature, facial dysmorphic features such as hypertelorism, a downward eyeslant and low-set posteriorly rotated ears, and a high incidence of congenital heart defects and hypertrophic cardiomyopathy. Other features can include a short neck with webbing or redundancy of skin, deafness, motor delay, variable intellectual deficits, multiple skeletal defects, cryptorchidism, and bleeding diathesis. Individuals with Noonan syndrome are at risk of juvenile myelomonocytic leukemia, a myeloproliferative disorder characterized by excessive production of myelomonocytic cells.
See also OMIM:611553
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar.1
Natural variantiVAR_037809259S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar.1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037820612S → T in NS5. 1 Publication1
LEOPARD syndrome 2 (LPRD2)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by lentigines, electrocardiographic conduction abnormalities, ocular hypertelorism, pulmonic stenosis, abnormalities of genitalia, retardation of growth, and sensorineural deafness.
See also OMIM:611554
Cardiomyopathy, dilated 1NN (CMD1NN)1 Publication
The disease is caused by mutations affecting the gene represented in this entry.
Disease descriptionA disorder characterized by ventricular dilation and impaired systolic function, resulting in congestive heart failure and arrhythmia. Patients are at risk of premature death.
See also OMIM:615916
Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865Ensembl.1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar.1

Mutagenesis

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Mutagenesisi338 – 339SS → AA: Reduced kinase activity; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi338 – 339SS → DE: Non-inhibited by PPP5C. Constitutively active and non-inhibited by PPP5C; when associated with 340-D-D-341. 1 Publication2
Mutagenesisi340 – 341YY → DD: Constitutively active and highly phosphorylated on S-338, inhibited by PPP5C. Reduced kinase activity; when associated with 338-A-A-339. Constitutively active and non-inhibited by PPP5C; when associated with 338-D-E-339. 1 Publication2
Mutagenesisi491T → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-494. 1 Publication1
Mutagenesisi494S → D: Increased kinase activity but can still be inhibited by PPP5C; when associated with D-491. 1 Publication1
Mutagenesisi563R → K: Loss of methylation. Increased stability and catalytic activity in response to EGF treatment. 1 Publication1

Keywords - Diseasei

Cardiomyopathy, Deafness, Disease mutation, Proto-oncogene

Organism-specific databases

DisGeNETi5894
GeneReviewsiRAF1
MalaCardsiRAF1
MIMi611553 phenotype
611554 phenotype
615916 phenotype
OpenTargetsiENSG00000132155
Orphaneti154 Familial isolated dilated cardiomyopathy
648 Noonan syndrome
500 Noonan syndrome with multiple lentigines
251612 Pilocytic astrocytoma
PharmGKBiPA34183

Chemistry databases

ChEMBLiCHEMBL1906
DrugBankiDB08912 Dabrafenib
DB05268 iCo-007
DB04973 LErafAON
DB08896 Regorafenib
DB00398 Sorafenib
DB05190 XL281
GuidetoPHARMACOLOGYi2184

Polymorphism and mutation databases

BioMutaiRAF1
DMDMi125651

PTM / Processingi

Molecule processing

Feature keyPosition(s)DescriptionActionsGraphical viewLength
ChainiPRO_00000865961 – 648RAF proto-oncogene serine/threonine-protein kinaseAdd BLAST648

Amino acid modifications

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Modified residuei29Phosphoserine; by MAPK1By similarity1
Modified residuei43Phosphoserine; by PKA and MAPK11 Publication1
Modified residuei252PhosphoserineCombined sources1
Modified residuei259Phosphoserine; by PKA, PKC and PKB/AKT17 Publications1
Modified residuei268Phosphothreonine; by autocatalysis1 Publication1
Modified residuei269Phosphothreonine; by PKA1 Publication1
Modified residuei289Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei296PhosphoserineCombined sources1
Modified residuei301Phosphoserine; by MAPK1Combined sources1 Publication1
Modified residuei338Phosphoserine; by PAK1, PAK2, PAK3 and PAK55 Publications1
Modified residuei339Phosphoserine; by PAK1, PAK2 and PAK31 Publication1
Modified residuei340Phosphotyrosine; by SRC1 Publication1
Modified residuei341Phosphotyrosine; by SRC1 Publication1
Modified residuei471Phosphoserine1 Publication1
Modified residuei491Phosphothreonine1 Publication1
Modified residuei494Phosphoserine1 Publication1
Modified residuei499Phosphoserine; by PKC1 Publication1
Modified residuei563Symmetric dimethylarginine; by PRMT51 Publication1
Modified residuei621Phosphoserine4 Publications1
Modified residuei642Phosphoserine; by MAPK1Combined sources1

Post-translational modificationi

Phosphorylation at Thr-269, Ser-338, Tyr-341, Thr-491 and Ser-494 results in its activation. Phosphorylation at Ser-29, Ser-43, Ser-289, Ser-296, Ser-301 and Ser-642 by MAPK1/ERK2 results in its inactivation. Phosphorylation at Ser-259 induces the interaction with YWHAZ and inactivates kinase activity. Dephosphorylation of Ser-259 by the complex containing protein phosphatase 1, SHOC2 and M-Ras/MRAS relieves inactivation, leading to stimulate RAF1 activity. Phosphorylation at Ser-338 by PAK1 and PAK5 and Ser-339 by PAK1 is required for its mitochondrial localization. Phosphorylation at Ser-621 in response to growth factor treatment stabilizes the protein, possibly by preventing proteasomal degradation. Phosphorylation at Ser-289, Ser-296, Ser-301, Ser-338 and Ser-621 are somehow linked to the methylation potential of cells. Treatment of cells with HGF in the presence of the methylation inhibitor 5'-methylthioadenosine (MTA) results in increased phosphorylation at Ser-338 and Ser-621 and decreased phosphorylation at Ser-296, Ser-301 and Ser-338. Dephosphorylation at Ser-338 by PPP5C results in an activity decrease.15 Publications
Methylated at Arg-563 in response to EGF treatment. This modification leads to destabilization of the protein, possibly through proteasomal degradation.1 Publication

Keywords - PTMi

Methylation, Phosphoprotein

Proteomic databases

EPDiP04049
MaxQBiP04049
PaxDbiP04049
PeptideAtlasiP04049
PRIDEiP04049
ProteomicsDBi51637
51638 [P04049-2]

PTM databases

iPTMnetiP04049
PhosphoSitePlusiP04049

Miscellaneous databases

PMAP-CutDBiP04049

Expressioni

Tissue specificityi

In skeletal muscle, isoform 1 is more abundant than isoform 2.1 Publication

Gene expression databases

BgeeiENSG00000132155 Expressed in 234 organ(s), highest expression level in cerebellar hemisphere
CleanExiHS_RAF1
ExpressionAtlasiP04049 baseline and differential
GenevisibleiP04049 HS

Organism-specific databases

HPAiCAB019291
HPA002640

Interactioni

Subunit structurei

Monomer. Homodimer. Heterodimerizes with BRAF and this heterodimer possesses a highly increased kinase activity compared to the respective homodimers or monomers (PubMed:16508002). Heterodimerization is mitogen-regulated and enhanced by 14-3-3 proteins (PubMed:16508002). MAPK1/ERK2 activation can induce a negative feedback that promotes the dissociation of the heterodimer (PubMed:16508002). Forms a multiprotein complex with Ras (M-Ras/MRAS), SHOC2 and protein phosphatase 1 (PPP1CA, PPP1CB and PPP1CC) (PubMed:16630891). Interacts with Ras proteins; the interaction is antagonized by RIN1 (PubMed:11784866). Weakly interacts with RIT1. Interacts (via N-terminus) with RGS14 (via RBD domains); the interaction mediates the formation of a ternary complex with BRAF, a ternary complex inhibited by GNAI1 (By similarity). Probably forms a complex composed of chaperones HSP90 and HSP70, co-chaperones CDC37, PPP5C, TSC1 and client protein TSC2, CDK4, AKT, RAF1 and NR3C1; this complex does not contain co-chaperones STIP1/HOP and PTGES3/p23 (PubMed:29127155). Interacts with STK3/MST2; the interaction inhibits its pro-apoptotic activity (PubMed:15618521). Interacts (when phosphorylated at Ser-259) with YWHAZ (unphosphorylated at 'Thr-232') (PubMed:9360956). Interacts with MAP2K1/MEK1 and MAP2K2/MEK2 (By similarity). Interacts with MAP3K5/ASF1 (via N-terminus) and this interaction inhibits the proapoptotic function of MAP3K5/ASK1 (PubMed:11427728). Interacts with PAK1 (via kinase domain) (PubMed:11733498). The phosphorylated form interacts with PIN1 (By similarity). The Ser-338 and Ser-339 phosphorylated form (by PAK1) interacts with BCL2 (PubMed:15849194). Interacts with PEBP1/RKIP and this interaction is enhanced if RAF1 is phosphorylated on residues Ser-338, Ser-339, Tyr-340 and Tyr-341 (PubMed:18294816). Interacts with ADCY2, ADCY5, ADCY6, DGKH, RCAN1/DSCR1, PPP1R12A, PKB/AKT1, PPP2CA, PPP2R1B, SPRY2, SPRY4, CNKSR1/CNK1, KSR2 and PHB/prohibitin (PubMed:10801873, PubMed:11719507, PubMed:12717443, PubMed:15385642, PubMed:15935327, PubMed:19710016, PubMed:10576742). Interacts with ROCK2 (By similarity). In its active form, interacts with PRMT5 (PubMed:21917714). Interacts with FAM83B; displaces 14-3-3 proteins from RAF1 and activates RAF1 (PubMed:22886302). Interacts with PDE8A; the interaction promotes RAF1 activity (PubMed:23509299). Interacts with MFHAS1 (PubMed:23327923).By similarity21 Publications

Binary interactionsi

GO - Molecular functioni

View the complete GO annotation on QuickGO ...

Protein-protein interaction databases

BioGridi111831, 176 interactors
CORUMiP04049
DIPiDIP-1048N
IntActiP04049, 119 interactors
MINTiP04049
STRINGi9606.ENSP00000251849

Chemistry databases

BindingDBiP04049

Structurei

Secondary structure

1648
Legend: HelixTurnBeta strandPDB Structure known for this area
Show more details

3D structure databases

DisProtiDP00171
ProteinModelPortaliP04049
SMRiP04049
ModBaseiSearch...
MobiDBiSearch...

Miscellaneous databases

EvolutionaryTraceiP04049

Family & Domainsi

Domains and Repeats

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Domaini56 – 131RBDPROSITE-ProRule annotationAdd BLAST76
Domaini349 – 609Protein kinasePROSITE-ProRule annotationAdd BLAST261

Region

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Regioni331 – 349Interaction with PEBP1/RKIPAdd BLAST19

Sequence similaritiesi

Belongs to the protein kinase superfamily. TKL Ser/Thr protein kinase family. RAF subfamily.Curated

Zinc finger

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Zinc fingeri138 – 184Phorbol-ester/DAG-typePROSITE-ProRule annotationAdd BLAST47

Keywords - Domaini

Zinc-finger

Phylogenomic databases

eggNOGiKOG0193 Eukaryota
ENOG410Y4UP LUCA
GeneTreeiENSGT00930000150812
HOGENOMiHOG000252972
HOVERGENiHBG001886
InParanoidiP04049
KOiK04366
OMAiFQMFQLM
OrthoDBiEOG091G09SB
PhylomeDBiP04049
TreeFamiTF317006

Family and domain databases

CDDicd00029 C1, 1 hit
InterProiView protein in InterPro
IPR020454 DAG/PE-bd
IPR011009 Kinase-like_dom_sf
IPR002219 PE/DAG-bd
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR003116 RBD_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR029071 Ubiquitin-like_domsf
PfamiView protein in Pfam
PF00130 C1_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF02196 RBD, 1 hit
PRINTSiPR00008 DAGPEDOMAIN
SMARTiView protein in SMART
SM00109 C1, 1 hit
SM00455 RBD, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50898 RBD, 1 hit
PS00479 ZF_DAG_PE_1, 1 hit
PS50081 ZF_DAG_PE_2, 1 hit

Sequences (2+)i

Sequence statusi: Complete.

This entry describes 2 isoformsi produced by alternative splicing. AlignAdd to basket

This entry has 2 described isoforms and 2 potential isoforms that are computationally mapped.Show allAlign All

Isoform 1 (identifier: P04049-1) [UniParc]FASTAAdd to basket
Also known as: 6C

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.

« Hide
        10         20         30         40         50
MEHIQGAWKT ISNGFGFKDA VFDGSSCISP TIVQQFGYQR RASDDGKLTD 
        60         70         80         90        100
PSKTSNTIRV FLPNKQRTVV NVRNGMSLHD CLMKALKVRG LQPECCAVFR 
       110        120        130        140        150
LLHEHKGKKA RLDWNTDAAS LIGEELQVDF LDHVPLTTHN FARKTFLKLA 
       160        170        180        190        200
FCDICQKFLL NGFRCQTCGY KFHEHCSTKV PTMCVDWSNI RQLLLFPNST 
       210        220        230        240        250
IGDSGVPALP SLTMRRMRES VSRMPVSSQH RYSTPHAFTF NTSSPSSEGS 
       260        270        280        290        300
LSQRQRSTST PNVHMVSTTL PVDSRMIEDA IRSHSESASP SALSSSPNNL 
       310        320        330        340        350
SPTGWSQPKT PVPAQRERAP VSGTQEKNKI RPRGQRDSSY YWEIEASEVM 
       360        370        380        390        400
LSTRIGSGSF GTVYKGKWHG DVAVKILKVV DPTPEQFQAF RNEVAVLRKT 
       410        420        430        440        450
RHVNILLFMG YMTKDNLAIV TQWCEGSSLY KHLHVQETKF QMFQLIDIAR 
       460        470        480        490        500
QTAQGMDYLH AKNIIHRDMK SNNIFLHEGL TVKIGDFGLA TVKSRWSGSQ 
       510        520        530        540        550
QVEQPTGSVL WMAPEVIRMQ DNNPFSFQSD VYSYGIVLYE LMTGELPYSH 
       560        570        580        590        600
INNRDQIIFM VGRGYASPDL SKLYKNCPKA MKRLVADCVK KVKEERPLFP 
       610        620        630        640 
QILSSIELLQ HSLPKINRSA SEPSLHRAAH TEDINACTLT TSPRLPVF
Length:648
Mass (Da):73,052
Last modified:November 1, 1986 - v1
Checksum:iEF821B5349711BC3
GO
Isoform 2 (identifier: P04049-2) [UniParc]FASTAAdd to basket
Also known as: 1A

The sequence of this isoform differs from the canonical sequence as follows:
     278-278: E → ENNNLSASPRAWSRRFCLRGR

Show »
Length:668
Mass (Da):75,395
Checksum:iBD64D7A649342F5D
GO

Computationally mapped potential isoform sequencesi

There are 2 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
EntryEntry nameProtein names
Gene namesLengthAnnotation
H7C155H7C155_HUMAN
RAF proto-oncogene serine/threonine...
RAF1
527Annotation score:
A0A0B4J1W9A0A0B4J1W9_HUMAN
RAF proto-oncogene serine/threonine...
RAF1
69Annotation score:

Experimental Info

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Sequence conflicti240F → L in AAA60247 (PubMed:2993863).Curated1
Sequence conflicti542M → I in AAA60247 (PubMed:2993863).Curated1

Natural variant

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Natural variantiVAR_071844237A → T in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777588EnsemblClinVar.1
Natural variantiVAR_037807256R → S in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516826EnsemblClinVar.1
Natural variantiVAR_037808257S → L in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced ERK activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338796EnsemblClinVar.1
Natural variantiVAR_041037259S → A in an ovarian serous carcinoma sample; somatic mutation; increased ERK activation. 2 Publications1
Natural variantiVAR_037809259S → F in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516827EnsemblClinVar.1
Natural variantiVAR_037810260T → I in hypertrophic cardiomyopathy. 1 PublicationCorresponds to variant dbSNP:rs869025501EnsemblClinVar.1
Natural variantiVAR_037811260T → R in NS5. 1 Publication1
Natural variantiVAR_037812261P → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037813261P → L in NS5; shows greater kinase activity and enhanced MAPK1 activation than wild-type. 1 PublicationCorresponds to variant dbSNP:rs397516828EnsemblClinVar.1
Natural variantiVAR_037814261P → S in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 3 PublicationsCorresponds to variant dbSNP:rs121434594EnsemblClinVar.1
Natural variantiVAR_037815263V → A in NS5; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 1 Publication1
Natural variantiVAR_018840308P → L2 PublicationsCorresponds to variant dbSNP:rs5746220EnsemblClinVar.1
Natural variantiVAR_071845310T → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs778155315Ensembl.1
Natural variantiVAR_071846332P → A in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs1057403865Ensembl.1
Natural variantiVAR_041038335Q → H in a lung adenocarcinoma sample; somatic mutation. 1 Publication1
Natural variantiVAR_037816486D → G in NS5. 1 PublicationCorresponds to variant dbSNP:rs397516815EnsemblClinVar.1
Natural variantiVAR_037817486D → N in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338798EnsemblClinVar.1
Natural variantiVAR_037818491T → I in NS5; has reduced or absent kinase activity. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_037819491T → R in NS5. 1 PublicationCorresponds to variant dbSNP:rs80338799EnsemblClinVar.1
Natural variantiVAR_071847603L → P in CMD1NN; shows impaired kinase activity and reduced MAPK3 activation with this mutation. 1 PublicationCorresponds to variant dbSNP:rs587777586EnsemblClinVar.1
Natural variantiVAR_037820612S → T in NS5. 1 Publication1
Natural variantiVAR_037821613L → V in NS5 and LPRD2; shows in vitro greater kinase activity and enhanced MAPK1 activation than wild-type. 2 PublicationsCorresponds to variant dbSNP:rs80338797EnsemblClinVar.1
Natural variantiVAR_071848626H → R in CMD1NN; shows a mild increase in kinase activity. 1 Publication1
Natural variantiVAR_071849641T → M in CMD1NN; shows a mild increase in kinase activity. 1 PublicationCorresponds to variant dbSNP:rs587777587EnsemblClinVar.1

Alternative sequence

Feature keyPosition(s)DescriptionActionsGraphical viewLength
Alternative sequenceiVSP_034649278E → ENNNLSASPRAWSRRFCLRG R in isoform 2. Curated1

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X03484 mRNA Translation: CAA27204.1
AY271661 Genomic DNA Translation: AAP03432.1
AK312248 mRNA Translation: BAG35180.1
EU332868 Genomic DNA Translation: ABY87557.1
CH471055 Genomic DNA Translation: EAW64134.1
BC018119 mRNA Translation: AAH18119.1
L00212
, L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1
X54851 Genomic DNA No translation available.
CCDSiCCDS2612.1 [P04049-1]
CCDS87047.1 [P04049-2]
PIRiA00637 TVHUF6
S60341
RefSeqiNP_002871.1, NM_002880.3 [P04049-1]
XP_005265412.1, XM_005265355.2
XP_011532276.1, XM_011533974.2 [P04049-1]
UniGeneiHs.159130

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155 [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155 [P04049-2]
GeneIDi5894
KEGGihsa:5894
UCSCiuc003bxf.5 human [P04049-1]

Keywords - Coding sequence diversityi

Alternative splicing, Polymorphism

Similar proteinsi

Cross-referencesi

Web resourcesi

NIEHS-SNPs
Atlas of Genetics and Cytogenetics in Oncology and Haematology

Sequence databases

Select the link destinations:
EMBLi
GenBanki
DDBJi
Links Updated
X03484 mRNA Translation: CAA27204.1
AY271661 Genomic DNA Translation: AAP03432.1
AK312248 mRNA Translation: BAG35180.1
EU332868 Genomic DNA Translation: ABY87557.1
CH471055 Genomic DNA Translation: EAW64134.1
BC018119 mRNA Translation: AAH18119.1
L00212
, L00206, L00207, L00208, L00209, L00210, L00211, L00213, M11376 Genomic DNA Translation: AAA60247.1
X54851 Genomic DNA No translation available.
CCDSiCCDS2612.1 [P04049-1]
CCDS87047.1 [P04049-2]
PIRiA00637 TVHUF6
S60341
RefSeqiNP_002871.1, NM_002880.3 [P04049-1]
XP_005265412.1, XM_005265355.2
XP_011532276.1, XM_011533974.2 [P04049-1]
UniGeneiHs.159130

3D structure databases

Select the link destinations:
PDBei
RCSB PDBi
PDBji
Links Updated
PDB entryMethodResolution (Å)ChainPositionsPDBsum
1C1YX-ray1.90B55-131[»]
1FAQNMR-A136-187[»]
1FARNMR-A136-187[»]
1GUAX-ray2.00B51-131[»]
1RFANMR-A55-132[»]
3CU8X-ray2.40P/Q256-264[»]
3IQJX-ray1.15P255-264[»]
3IQUX-ray1.05P255-260[»]
3IQVX-ray1.20P255-260[»]
3KUCX-ray1.92B51-131[»]
3KUDX-ray2.15B51-131[»]
3NKXX-ray2.40P/Q255-264[»]
3O8IX-ray2.00B255-264[»]
3OMVX-ray4.00A/B323-618[»]
4FJ3X-ray1.95P229-264[»]
4G0NX-ray2.45B54-131[»]
4G3XX-ray3.25B55-131[»]
4IEAX-ray1.70P618-625[»]
4IHLX-ray2.20P229-264[»]
DisProtiDP00171
ProteinModelPortaliP04049
SMRiP04049
ModBaseiSearch...
MobiDBiSearch...

Protein-protein interaction databases

BioGridi111831, 176 interactors
CORUMiP04049
DIPiDIP-1048N
IntActiP04049, 119 interactors
MINTiP04049
STRINGi9606.ENSP00000251849

Chemistry databases

BindingDBiP04049
ChEMBLiCHEMBL1906
DrugBankiDB08912 Dabrafenib
DB05268 iCo-007
DB04973 LErafAON
DB08896 Regorafenib
DB00398 Sorafenib
DB05190 XL281
GuidetoPHARMACOLOGYi2184

Protein family/group databases

MoonDBiP04049 Predicted

PTM databases

iPTMnetiP04049
PhosphoSitePlusiP04049

Polymorphism and mutation databases

BioMutaiRAF1
DMDMi125651

Proteomic databases

EPDiP04049
MaxQBiP04049
PaxDbiP04049
PeptideAtlasiP04049
PRIDEiP04049
ProteomicsDBi51637
51638 [P04049-2]

Protocols and materials databases

DNASUi5894
Structural Biology KnowledgebaseSearch...

Genome annotation databases

EnsembliENST00000251849; ENSP00000251849; ENSG00000132155 [P04049-1]
ENST00000442415; ENSP00000401888; ENSG00000132155 [P04049-2]
GeneIDi5894
KEGGihsa:5894
UCSCiuc003bxf.5 human [P04049-1]

Organism-specific databases

CTDi5894
DisGeNETi5894
EuPathDBiHostDB:ENSG00000132155.11
GeneCardsiRAF1
GeneReviewsiRAF1
HGNCiHGNC:9829 RAF1
HPAiCAB019291
HPA002640
MalaCardsiRAF1
MIMi164760 gene
611553 phenotype
611554 phenotype
615916 phenotype
neXtProtiNX_P04049
OpenTargetsiENSG00000132155
Orphaneti154 Familial isolated dilated cardiomyopathy
648 Noonan syndrome
500 Noonan syndrome with multiple lentigines
251612 Pilocytic astrocytoma
PharmGKBiPA34183
GenAtlasiSearch...

Phylogenomic databases

eggNOGiKOG0193 Eukaryota
ENOG410Y4UP LUCA
GeneTreeiENSGT00930000150812
HOGENOMiHOG000252972
HOVERGENiHBG001886
InParanoidiP04049
KOiK04366
OMAiFQMFQLM
OrthoDBiEOG091G09SB
PhylomeDBiP04049
TreeFamiTF317006

Enzyme and pathway databases

BRENDAi2.7.10.2 2681
ReactomeiR-HSA-2672351 Stimuli-sensing channels
R-HSA-392517 Rap1 signalling
R-HSA-430116 GP1b-IX-V activation signalling
R-HSA-442742 CREB phosphorylation through the activation of Ras
R-HSA-5621575 CD209 (DC-SIGN) signaling
R-HSA-5673000 RAF activation
R-HSA-5674135 MAP2K and MAPK activation
R-HSA-5674499 Negative feedback regulation of MAPK pathway
R-HSA-5675221 Negative regulation of MAPK pathway
R-HSA-6802946 Signaling by moderate kinase activity BRAF mutants
R-HSA-6802948 Signaling by high-kinase activity BRAF mutants
R-HSA-6802949 Signaling by RAS mutants
R-HSA-6802952 Signaling by BRAF and RAF fusions
R-HSA-6802955 Paradoxical activation of RAF signaling by kinase inactive BRAF
SignaLinkiP04049
SIGNORiP04049

Miscellaneous databases

ChiTaRSiRAF1 human
EvolutionaryTraceiP04049
GeneWikiiC-Raf
GenomeRNAii5894
PMAP-CutDBiP04049
PROiPR:P04049
SOURCEiSearch...

Gene expression databases

BgeeiENSG00000132155 Expressed in 234 organ(s), highest expression level in cerebellar hemisphere
CleanExiHS_RAF1
ExpressionAtlasiP04049 baseline and differential
GenevisibleiP04049 HS

Family and domain databases

CDDicd00029 C1, 1 hit
InterProiView protein in InterPro
IPR020454 DAG/PE-bd
IPR011009 Kinase-like_dom_sf
IPR002219 PE/DAG-bd
IPR000719 Prot_kinase_dom
IPR017441 Protein_kinase_ATP_BS
IPR003116 RBD_dom
IPR001245 Ser-Thr/Tyr_kinase_cat_dom
IPR008271 Ser/Thr_kinase_AS
IPR029071 Ubiquitin-like_domsf
PfamiView protein in Pfam
PF00130 C1_1, 1 hit
PF07714 Pkinase_Tyr, 1 hit
PF02196 RBD, 1 hit
PRINTSiPR00008 DAGPEDOMAIN
SMARTiView protein in SMART
SM00109 C1, 1 hit
SM00455 RBD, 1 hit
SM00220 S_TKc, 1 hit
SUPFAMiSSF54236 SSF54236, 1 hit
SSF56112 SSF56112, 1 hit
PROSITEiView protein in PROSITE
PS00107 PROTEIN_KINASE_ATP, 1 hit
PS50011 PROTEIN_KINASE_DOM, 1 hit
PS00108 PROTEIN_KINASE_ST, 1 hit
PS50898 RBD, 1 hit
PS00479 ZF_DAG_PE_1, 1 hit
PS50081 ZF_DAG_PE_2, 1 hit
ProtoNetiSearch...

Entry informationi

Entry nameiRAF1_HUMAN
AccessioniPrimary (citable) accession number: P04049
Secondary accession number(s): B0LPH8
, B2R5N3, Q15278, Q9UC20
Entry historyiIntegrated into UniProtKB/Swiss-Prot: November 1, 1986
Last sequence update: November 1, 1986
Last modified: November 7, 2018
This is version 228 of the entry and version 1 of the sequence. See complete history.
Entry statusiReviewed (UniProtKB/Swiss-Prot)
Annotation programChordata Protein Annotation Program
DisclaimerAny 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.

Miscellaneousi

Keywords - Technical termi

3D-structure, Complete proteome, Direct protein sequencing, Reference proteome

Documents

  1. SIMILARITY comments
    Index of protein domains and families
  2. Human chromosome 3
    Human chromosome 3: entries, gene names and cross-references to MIM
  3. Human entries with polymorphisms or disease mutations
    List of human entries with polymorphisms or disease mutations
  4. Human polymorphisms and disease mutations
    Index of human polymorphisms and disease mutations
  5. MIM cross-references
    Online Mendelian Inheritance in Man (MIM) cross-references in UniProtKB/Swiss-Prot
  6. PDB cross-references
    Index of Protein Data Bank (PDB) cross-references
  7. Human and mouse protein kinases
    Human and mouse protein kinases: classification and index
UniProt is an ELIXIR core data resource
Main funding by: National Institutes of Health

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