UniProtKB ­ P31946 (1433B_HUMAN)

Protein 14­3­3 beta/alpha YWHAB Organism Homo sapiens (Human)

Status s Reviewed ­ Annotation score: ­ Experimental evidence at protein level

Function

Adapter protein implicated in the regulation of a large spectrum of both general and specialized signaling pathways. Binds to a large number of partners, usually by recognition of a phosphoserine or phosphothreonine motif. Binding generally results in the modulation of the activity of the binding partner. Negative regulator of osteogenesis. Blocks the nuclear translocation of the phosphorylated form (by AKT1) of SRPK2 and antagonizes its stimulatory effect on cyclin D1 expression resulting in blockage of neuronal apoptosis elicited by SRPK2. Negative regulator of signaling cascades that mediate activation of MAP kinases via AKAP13. Evidence: 3 Publications

GO ­ Molecular function cadherin binding Evidence: Source: BHF­UCL enzyme binding Evidence: Source: BHF­UCL histone deacetylase binding Evidence: Source: BHF­UCL phosphoprotein binding Evidence: Source: BHF­UCL phosphoserine binding Evidence: Source: BHF­UCL protein complex binding Evidence: Source: Ensembl protein C­terminus binding Evidence: Source: Ensembl protein domain specific binding Evidence: Source: UniProtKB transcription corepressor activity Evidence: Source: Ensembl

GO ­ Biological process cytoplasmic sequestering of protein Evidence: Source: BHF­UCL hippo signaling Evidence: Source: Reactome MAPK cascade Evidence: Source: Reactome membrane organization Evidence: Source: Reactome negative regulation of G­protein coupled receptor protein signaling pathway Evidence: Source: UniProtKB negative regulation of protein dephosphorylation Evidence: Source: BHF­UCL negative regulation of transcription, DNA­templated Evidence: Source: Ensembl positive regulation of catalytic activity Evidence: Source: BHF­UCL positive regulation of protein insertion into mitochondrial membrane involved in apoptotic signaling pathway Evidence: Source: Reactome protein heterooligomerization Evidence: Source: Ensembl protein targeting Evidence: Source: Ensembl regulation of mRNA stability Evidence: Source: Reactome viral process Evidence: Source: UniProtKB­KW

Keywords Biological Host­virus interaction process

Enzyme and pathway databases Reactome R­HSA­111447. Activation of BAD and translocation to mitochondria. R­HSA­1445148. Translocation of GLUT4 to the plasma membrane. R­HSA­165159. mTOR signalling. R­HSA­166208. mTORC1­mediated signalling. R­HSA­170968. Frs2­mediated activation. R­HSA­170984. ARMS­mediated activation. R­HSA­2028269. Signaling by Hippo. R­HSA­392517. Rap1 signalling. R­HSA­450385. Butyrate Response Factor 1 (BRF1) binds and destabilizes mRNA. R­HSA­450513. Tristetraprolin (TTP, ZFP36) binds and destabilizes mRNA. R­HSA­5625740. RHO GTPases activate PKNs. R­HSA­5628897. TP53 Regulates Metabolic . R­HSA­5673000. RAF activation. R­HSA­5674135. MAP2K and MAPK activation. R­HSA­5675221. Negative regulation of MAPK pathway. R­HSA­6802946. Signaling by moderate kinase activity BRAF mutants. R­HSA­6802948. Signaling by high­kinase activity BRAF mutants. R­HSA­6802949. Signaling by RAS mutants. R­HSA­6802952. Signaling by BRAF and RAF fusions. R­HSA­6802955. Paradoxical activation of RAF signaling by kinase inactive BRAF. R­HSA­75035. Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex. SignaLink P31946. SIGNOR P31946. Names & Taxonomy

Protein names Recommended name: 14­3­3 protein beta/alpha Alternative name(s): Protein 1054 Protein kinase C inhibitor protein 1 Short name:KCIP­1 Cleaved into the following chain: 14­3­3 protein beta/alpha, N­terminally processed Gene names Name:YWHAB Organism Homo sapiens (Human) Taxonomic identifier 9606 [NCBI] Taxonomic lineage Eukaryota › Metazoa › Chordata › Craniata › Vertebrata › Euteleostomi › Mammalia › Eutheria › Euarchontoglires › Primates › Haplorrhini › Catarrhini › Hominidae › Homo Proteomes UP000005640 Component: 20

Organism­specific databases HGNC HGNC:12849. YWHAB. Subcellular location

Cytoplasm Evidence: 1 Publication Melanosome Evidence: 1 Publication Note: Identified by mass spectrometry in melanosome fractions from stage I to stage IV.

GO ­ Cellular component cytoplasm Evidence: Source: UniProtKB cytoplasmic vesicle membrane Evidence: Source: Reactome cytosol Evidence: Source: HPA extracellular exosome Evidence: Source: UniProtKB focal adhesion Evidence: Source: UniProtKB melanosome Evidence: Source: UniProtKB­SubCell membrane Evidence: Source: UniProtKB mitochondrion Evidence: Source: GOC nucleus Evidence: Source: Ensembl perinuclear region of cytoplasm Evidence: Source: UniProtKB protein complex Evidence: Source: Ensembl transcriptional repressor complex Evidence: Source: Ensembl

Keywords ­ Cellular component Cytoplasm Pathology & Biotech

Organism­specific databases DisGeNET 7529. OpenTargets ENSG00000166913. PharmGKB PA37438.

Polymorphism and mutation databases DMDM 1345590. PTM / Processing

Molecule processing Feature key Position(s) Description Graphical view

Chain (PRO_0000367900) 1 – 246 14­3­3 protein beta/alpha

Initiator methionine Removed; alternate Evidence: Combined sources Evidence: 1 Publication

Chain (PRO_0000000003) 2 – 246 14­3­3 protein beta/alpha, N­terminally processed

Amino acid modifications Feature key Position(s) Description Graphical view

Modified residue 1 N­acetylmethionine; in 14­3­3 protein beta/alpha; alternate Evidence: Combined sources Evidence: 1 Publication Modified residue 2 N­acetylthreonine; in 14­3­3 protein beta/alpha, N­terminally processed Evidence: Combined sources Evidence: 1 Publication Modified residue 2 Phosphothreonine Evidence: Combined sources Modified residue 60 Phosphoserine Evidence: By similarity Modified residue 70 N6­acetyllysine Evidence: Combined sources Modified residue 84 Nitrated tyrosine Evidence: By similarity Modified residue 106 Nitrated tyrosine Evidence: By similarity Modified residue 117 N6­acetyllysine Evidence: Combined sources Modified residue 186 Phosphoserine Evidence: By similarity Modified residue 232 Phosphoserine Evidence: Combined sources Isoform Short (identifier: P31946­2) Modified residue 1 N­acetylmethionine Evidence: Combined sources

Post­translational modification The alpha, brain­specific form differs from the beta form in being phosphorylated. Phosphorylated on Ser­60 by protein kinase C delta type catalytic subunit in a sphingosine­dependent fashion. Evidence: By similarity

Keywords ­ PTM Acetylation, Nitration, Phosphoprotein

Proteomic databases EPD P31946. PaxDb P31946. PeptideAtlas P31946. PRIDE P31946. TopDownProteomics P31946­1. [P31946­1] P31946­2. [P31946­2]

2D gel databases OGP P31946. REPRODUCTION­ IPI00216318. 2DPAGE

PTM databases iPTMnet P31946. PhosphoSitePlus P31946. SwissPalm P31946. Expression

Gene expression databases Bgee ENSG00000166913. CleanEx HS_YWHAB. ExpressionAtlas P31946. baseline and differential. Genevisible P31946. HS.

Organism­specific databases HPA CAB003759. HPA007925. HPA011212. Interaction

Subunit structure Homodimer (PubMed:17717073). Interacts with SAMSN1 and PRKCE (By similarity). Interacts with AKAP13 (PubMed:21224381). Interacts with SSH1 and TORC2/CRTC2 (PubMed:15454081, PubMed:15159416). Interacts with ABL1; the interaction results in cytoplasmic location of ABL1 and inhibition of cABL­mediated apoptosis (PubMed:15696159). Interacts with ROR2 (dimer); the interaction results in phosphorylation of YWHAB on tyrosine residues (PubMed:17717073). Interacts with GAB2 (PubMed:19172738). Interacts with YAP1 (phosphorylated form) (PubMed:17974916). Interacts with the phosphorylated (by AKT1) form of SRPK2 (PubMed:19592491). Interacts with PKA­phosphorylated AANAT (PubMed:11427721). Interacts with MYO1C (PubMed:24636949). Interacts with SIRT2 (PubMed:18249187). Interacts with the 'Thr­369' phosphorylated form of DAPK2 (PubMed:26047703). Interacts with PI4KB, TBC1D22A and TBC1D22B (PubMed:23572552). Interacts with the 'Ser­1134' and 'Ser­1161' phosphorylated form of SOS1 (PubMed:22827337). Interacts (via phosphorylated form) with YWHAB; this interaction occurs in a protein kinase AKT1­dependent manner (PubMed:15538381). Interacts with SLITRK1 (PubMed:19640509). Interacts with SYNPO2 (phosphorylated form); YWHAB competes with ACTN2 for interaction with SYNPO2 (By similarity). Interacts with RIPOR2 (via phosphorylated form) isoform 2; this interaction occurs in a chemokine­dependent manner and does not compete for binding of RIPOR2 with RHOA nor blocks inhibition of RIPOR2­mediated RHOA activity (PubMed:25588844). Evidence: By similarity Evidence: 18 Publications

(Microbial infection) Interacts with herpes simplex virus 1 protein UL46. Evidence: 1 Publication

Sites Feature key Position(s) Description Graphical view

Site 58 Interaction with phosphoserine on interacting protein Evidence: By similarity Site 129 Interaction with phosphoserine on interacting protein Evidence: By similarity

Binary interactions P31946 has binary interactions with 33

Subcellular location Diseases N N A N N A N N N N E N N N N N N 1 M A N E A A L N A A A S M N A N N N N N N N N A A A A N E A V A S U E M N A T M A A M A A I A A A U U A A M M M M E I M A S M M M M U E M A H U U U H M M M M M O H M S U B U M M U U M M U U _ M U U A U U O 9 U _ M H H H U A U U U U U U H H U U H M H U U 2 H _ O 3 U H H C H _ _ _ H ­ H M U _ _ _ _ _ H R ­ H H H H H O H H H H _ 3 _ _ _ _ 4 2 3 _ _ _ H M 4 2 2 2 1 A _ _ 2 _ _ _ _ _ H _ _ _ _ 5 1 2 6 M 3 B E 3 3 K _ _ K 1 T 1 C 4 K K P 2 F 2 1 5 3 _ A 3 1 2 1 3 5 _ 3 P P 3 D K A D D R I I R L X 1 F P A A C R B M M K K R N 6 H P N 7 C 3 3 P 3 A P P 3 A B B D A 7 A Y A E E D M N N C T R Y D R S A 4 R E S 4 T 1 C C C K L M M P R S S Y Q A B M M D D G G G H L M M R R R S T 1 T 1433B_HUMAN CBL_HUMAN CBX4_HUMAN CDK14_HUMAN KC1A_RABIT LRRK2_HUMAN M3K5_HUMAN MARK2_HUMAN PTN3_HUMAN RAF1_HUMAN SRPK2_HUMAN SYNP2_MOUSE YAP1_HUMAN Q76353_9HIV1 ADA22­3_HUMAN BRAF_HUMAN MPIP1_HUMAN MPIP2_HUMAN DACT1_HUMAN DYR1A­2_HUMAN GAB2_HUMAN GEM_HUMAN GEM_MOUSE HDAC4_HUMAN LE756_CAEEL M3K3_HUMAN MARK3_HUMAN RMD3_HUMAN RND3_HUMAN RND3_MOUSE SSH1_HUMAN TSC2_HUMAN 1433E_HUMAN TTP_MOUSE Show more details

GO ­ Molecular function cadherin binding Evidence: Source: BHF­UCL enzyme binding Evidence: Source: BHF­UCL histone deacetylase binding Evidence: Source: BHF­UCL phosphoprotein binding Evidence: Source: BHF­UCL phosphoserine binding Evidence: Source: BHF­UCL protein complex binding Evidence: Source: Ensembl protein C­terminus binding Evidence: Source: Ensembl protein domain specific binding Evidence: Source: UniProtKB

Protein­protein interaction databases BioGrid 113361. 340 interactors. DIP DIP­743N. IntAct P31946. 267 interactors. MINT MINT­99570. STRING 9606.ENSP00000300161. Structure

Secondary structure 1 246

Legend: Helix Turn Beta strand PDB Structure known for this area

Show more details

3D structure databases Select the link PDB entry Method Resolution (Å) Chain Positions PDBsum destinations: 2BQ0 X­ray 2.50 A/B 2­239 [»] PDBe 2C23 X­ray 2.65 A 2­239 [»] RCSB PDB PDBj 4DNK X­ray 2.20 A/B 1­246 [»] ProteinModelPortal P31946. SMR P31946. ModBase Search... MobiDB Search...

Miscellaneous databases EvolutionaryTrace P31946. Family & Domains

Sequence similarities Belongs to the 14­3­3 family. Evidence: Curated

Phylogenomic databases eggNOG KOG0841. Eukaryota. COG5040. LUCA. GeneTree ENSGT00760000119116. HOGENOM HOG000240379. HOVERGEN HBG050423. InParanoid P31946. KO K16197. OMA KKQQMGR. OrthoDB EOG091G0VKY. PhylomeDB P31946. TreeFam TF102003.

Family and domain databases Gene3D 1.20.190.20. 1 hit. InterPro View protein in InterPro IPR000308. 14­3­3. IPR023409. 14­3­3_CS. IPR023410. 14­3­3_domain. PANTHER PTHR18860. PTHR18860. 1 hit. Pfam View protein in Pfam PF00244. 14­3­3. 1 hit. PIRSF PIRSF000868. 14­3­3. 1 hit. PRINTS PR00305. 1433ZETA. SMART View protein in SMART SM00101. 14_3_3. 1 hit. SUPFAM SSF48445. SSF48445. 1 hit. PROSITE View protein in PROSITE PS00796. 1433_1. 1 hit. PS00797. 1433_2. 1 hit. Sequences (2)

Sequence status: Complete. Sequence processing: The displayed sequence is further processed into a mature form. This entry describes 2 isoforms produced by alternative initiation.

Isoform Long (identifier: P31946­1) [UniParc] 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 MTMDKSELVQ KAKLAEQAER YDDMAAAMKA VTEQGHELSN EERNLLSVAY 60 70 80 90 100 KNVVGARRSS WRVISSIEQK TERNEKKQQM GKEYREKIEA ELQDICNDVL 110 120 130 140 150 ELLDKYLIPN ATQPESKVFY LKMKGDYFRY LSEVASGDNK QTTVSNSQQA 160 170 180 190 200 YQEAFEISKK EMQPTHPIRL GLALNFSVFY YEILNSPEKA CSLAKTAFDE 210 220 230 240 AIAELDTLNE ESYKDSTLIM QLLRDNLTLW TSENQGDEGD AGEGEN

Length: 246 Mass (Da): 28,082 Last modified: January 23, 2007 ­ v3 Checksum: 6BE1A9BF97468017

Isoform Short (identifier: P31946­2) [UniParc] The sequence of this isoform differs from the canonical sequence as follows: 1­2: Missing.

Show » Length: 244 Mass (Da): 27,850 Checksum: CE0A59BF8C33FE2F Natural variant Feature key Position(s) Description Graphical view

Natural variant (VAR_064762) 99 V → I Found in a renal cell carcinoma sample; somatic mutation. Evidence: 1 Publication

Alternative sequence Feature key Position(s) Description Graphical view

Alternative sequence 1 – 2 Missing in isoform Short. Evidence: Curated (VSP_018632)

Sequence databases Select the link X57346 mRNA. Translation: CAA40621.1. destinations: AK292717 mRNA. Translation: BAF85406.1. EMBL AL008725 Genomic DNA. Translation: CAA15497.1. GenBank CH471077 Genomic DNA. Translation: EAW75893.1. DDBJ CH471077 Genomic DNA. Translation: EAW75894.1. CH471077 Genomic DNA. Translation: EAW75896.1. BC001359 mRNA. Translation: AAH01359.1. CCDS CCDS13339.1. [P31946­1] PIR S34755. RefSeq NP_003395.1. NM_003404.4. [P31946­1] NP_647539.1. NM_139323.3. [P31946­1] XP_016883528.1. XM_017028039.1. [P31946­1] UniGene Hs.643544.

Genome annotation databases Ensembl ENST00000353703; ENSP00000300161; ENSG00000166913. [P31946­1] ENST00000372839; ENSP00000361930; ENSG00000166913. [P31946­1] GeneID 7529. KEGG hsa:7529.

Keywords ­ Coding sequence diversity Alternative initiation, Polymorphism References

[1]M. Saha et al., “RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation,” Biochemical Journal, vol. 447, no. 1. Portland Press Ltd., pp. 159–166, 01-Oct-2012.