Gene family: brain proteins of the 14-3-3 family; (YWHAB YWHAE YWHAG YWHAH BP1433TA BP1433TH YWHAZ)


There are many discrepancies between various versions of nucleotide and amino acid sequences of particular members of this protein family in man, submitted to public databases by different research groups. All of the discrepancies are discussed in the relevant GEM_entries (see 'Family Tree' in the current 'Options' menu). Moreover, the same abbreviations (AS1, HS1, KCIP-1) are used for a symbolization of different proteins of the family. Some entry_records in public databases contain comments and references to particular members of the family, which are incorrect or confusing: !USER ATTENTION ADVISED!"


[1] Several members of this protein family in mammals are currently classified as follows ('aa' is 'amino acid residues'): -------------------------------------------------------------- Subtype Aminoterminal sequence Total Human ortholog alignment 1 alignment 2 aa ------- ----------- ------------ ----- ------------------ TAU --M_EKTEL.. --MEKTEL.. 245 GEM:00.0/BP1433TA* THETA --M_ERASL.. --MERASL.. 248 GEM:00.0/BP1433TH* ZETA --M_DKNEL.. --MDKNEL.. 245 GEM:02p25/YWHAZ BETA MTM_DKSEL.. MTMDKSEL.. 246 GEM:20q131/YWHAB ETA --MGDREQL.. MG_DREQL.. 246 GEM:22q12/YWHAH GAMMA --MVDREQL.. MV_DREQL.. 247 GEM:00.0/YWHAG EPSILON --MDDREDL.. MD_DREDL.. 255 GEM:17p13/YWHAE ALPHA = BETA isoform, phosphorilated GEM:20q131/YWHAB DELTA = ZETA isoform, phosphorilated GEM:02p25/YWHAZ -------------------------------------------------------------- Recently, Aitken A &:JBC,1995 presented some evidences demonstrating that 14-3-3 ALPHA and DELTA proteins are in vivo post-translationally modified, phosphorylated, products of the raf-activating 14-3-3 BETA and ZETA isoforms, respectively. Although GAMMA subtype was not yet unrevealed in man, Leffers H &:1993 mentioned that one of the polypeptides identified in their master two- -dimensional gel database of human keratinocyte proteins (particularly, IEF SSP 9124) is probably the human homolog of bovine gamma. %-----------------------------------------------------------------------
[2] The following basic identifiers may be helpful in a search for pub- lished materials relating to the family: ---------------------------------------------------------- GEM_DB ---- Subtype Synonyms Location MIM EC Symbol ACCN ------- ------------------ --------- ------ ------ -------------- beta HS1 KCIP1 c1054 ? - - BP1433B H03624 eta AS1 KCIP1 YWHAH: Chr 22 113508 - BP1433E H02895 tau HS1 ? - - BP1433TA H03651 theta HME1 c9112 stratifin ? - - BP1433TH H03623 zeta FAS Exo1 PLA2L:? ? - 3.1.1.? BP1433Z H03659 ----------------------------------------------------------------------
[3] In addition, nine short cDNA fragments, EST (Expressed Sequence Tag), were submitted to public Databases as homologues to the 14-3-3 family without a more specific notation. Three of the fragments are certainly identical to particular parts of ETA or TAU cDNAs (see the relevant GEM_ _entries using 'Family Tree'), while the other six cannot be classified. The latter sequences are described in the section 'Nonclassified'. <* > [METABOLIC EXPRESSION:]
[1] The 14-3-3 proteins are homodimeric molecules which function in the cytoplasm, mainly in the brain; at lower levels, they are also present in other tissues. In neurons, they are axonally transported to the nerve terminals. Using NORTHERN BLOT experiments, ICHIMURA-OHSHIMA Y &:1992 (Mol Genetics Lab, Niigata University, Japan) showed widespread expres- sion of the 14-3-3 protein ETA in cultured cell lines derived from vari- ous human tumors. Also, LEFFERS H &:1993 (see below) discovered a par- ticular member of this family - stratifin, expressed only in cultured epithelial cells. The protein was most abundant in adult and fetal tis- sues enriched in stratified squamous keratinising epithelium.Furthemore, TAKEDA J &:1993 (Howard Hughes Med Inst & Univ of Chicago) prepared a database of genes expressed in the pancreatic islets (of Langerhans) and partially sequenced 1000 cDNA clones from this library. Among the clones, a 150 bp-sequence was identified and submitted to GenBank as a member of the 14-3-3 protein family (see 'REFER_3' in GEM:00.0/BP1433TA).
[2] The proteins are probably multifunctional regulators of the cell sig- naling processes mediated by some of protein kinases. For example, they ACTIVATE tyrosine/tryptophan hydroxilases (GEM:11p155/TH; GEM:11p1/TRPH) in the presence of Ca2+/calmodulin-dependent protein kinase II. At the same time, some of the proteins are INHIBITERS of Ca2+/phospholipid- -dependent protein kinase C (GEM:17q2/PRKCA). At least one of the 14-3-3 proteins - zeta - is an INTRAcellular phospholipase A2 which employs a catalytic strategy distinct from that utilized by EXTRAcellular phospho- lipases A2 (Zupan LA &:1992). /Note_1: There are at least two human genes which are directly correlate with this latter enzymatic function (GEM:12q2/PLA2G1B; GEM:01p35/PLA2G2A). /Note_2: On the other hand, in a recent publication by Robinson K &:1994, the authors did not find PLA2 activity in brain 14-3-3 proteins tested including zeta isoform, 'on which the original observation was made.' %----------------------------------------------------------------------- <* > [SHORT HISTORY:] <**> [ORIGINALLY,] proteins of the 14-3-3 family were identified and named by Moore BW and Perez VJ in 1967 (Physiol and Biochem Aspects of Nervous Integration. Ed: Carlson FD, pp. 343-359, Prentice Hall). These authors proposed the nomenclature of brain acidic proteins having molecular mas- ses of around 30 kDa and an isoelectric point of around 5, in the two- -dimensional polyacrylamide gel electrophoresis (PAGE) system. Further studies also demonstrated that the proteins are homodimeric forms. <** > [FIRST, ICHIMURA T &:1988] (Dept of Chemistry, Faculty of Science, Tokyo Metropolitan University) resolved the BOVINE brain 14-3-3 proteins into seven polypeptide components by means of reversed-phase chromato- graphy and determined the amino acid sequence of one of these components (eta chain) by isolating its cDNA from a bovine cerebellum cDNA library. The bovine eta mRNA was 1.8 kb long (gnb:J03868). The authors showed that this mRNA encodes a polypeptide of 246 amino acids. A computer analysis showed that the protein does not have sequence similarity to other known proteins. The authors wrote that 'The eta chain appears to consist of two structural regions that are distinguishable in their clearly different charge features: the almost neutral aminoterminal region and the strongly acidic carboxyl-terminal region. The structural features of the eta polypeptide and its domain organization suggest that the 14-3-3 protein binds to the regulatory domain of the phosphorylated hydroxylases along its acidic carboxyl-terminal region and activates these enzymes by inducing their active conformation'. %----------------------------------------------------------------------- <** > NIELSEN PJ:1991 (Max Planck Institut fur Immunbiologie, Freiburg, FRG), cloned a HUMAN T-cell cDNA which encodes a protein closely re- lated to a family of proteins described both as coregulators of mono- amine biosynthesis in neurons and as inhibitors of protein kinase C. The predicted human protein (14-3-3 thau) is 28 kDa (pI of 4.5). Its putative amino acid sequence showes strong conservation from Drosophila to man. Several mRNAs hybridizing to the cDNA were found in human epi- thelial and T-cell lines. %----------------------------------------------------------------------- <** > [ZUPAN LA &:1992] (Dept of Medicine, Washington Univ School of Medi- cine, St.Louis, Missouri 63110) referred to their previus study (Loeb LA, Gross RW: JBC, 261, 10467-70, 1986) in which they reported that the major phospholipase A2 activity (in sheep platelets) is mediated by at least three isoforms of a 30-kDa dimeric polypeptide which are responsive to physiologic increments in calcium ion and possess a significant substrate selectivity. Based on these data, they cloned the HUMAN homologue of one such isoform and showed that it catalyzes the cleavage of the sn-2 fatty acid of choline and ethanolamine glycerophospholipids through the forma- tion of a stable acyl-enzyme intermediate. They also showed that 'trans- esterification of the sn-2 acyl group of phosphatidylcholine to the re- combinant 30-kDa polypeptide is over 50-fold selective for arachidonic acid, is augmented by calcium ion, and results in the formation of an arachidonoyl-thioester intermediate'. Sequence analysis showed that the polypeptide mediating this transesterification is a member of the 14-3-3 protein family. Finally, the authors conclude that 'their results demon- strate that at least one INTRACELLULAR mammalian phospholipase A2 employs a catalytic strategy distinct from that utilized by extracellular phospho- lipases A2 (ie, formation of an acyl-enzyme intermediate by nucleophilic attack versus activation of a water molecule) and that arachidonic acid in endogenous phospholipid storage depots can be sequentially transferred through an acyl-enzyme intermediate without the prior obligatory release of free arachidonic acid'. Or, by other words, activation of a water mol- ecule for cleavage of ester linkages leads to the obligatory release of free fatty acids, in known examples of extracellular phospholipase A2, whereas the intracellular phospholipase, a member of the family of 14-3-3 proteins, forms a stable arachidonoyl-enzyme intermediate during catalysis. In principle, this enzyme could transfer arachidonic acid sequentially to acceptors other than water, without the release of free arachidonic acid. %----------------------------------------------------------------------- <** > [ISOBE T &:1992] (Dept of Chemistry, Faculty of Science, Tokyo Metro- politan University, Japan), in their publication entitled 'Activation of protein kinase C by the 14-3-3 proteins homologous with Exo1 protein that stimulates calcium-dependent exocytosis', reported that '... it has been demonstrated that a member of the 14-3-3 family, termed Exo1, stimulates Ca(2+)-dependent exocytosis in permeabilized adrenal chromaffin cells, suggesting that this protein family may influence the protein kinase C- -mediated control of Ca(2+)-dependent exocytosis'. Based on these data, the authors showed that the 14-3-3 proteins ACTIVATE protein kinase C at 2-fold more than the known level of the activated protein kinase, ie. the activity of protein kinase C in the presence of Ca2+ and phospholip- ids. They suggested the possibility 'that the cellular activity of pro- tein kinase C is regulated by diverse members of the 14-3-3 family' and that the known ability of Exo1 to reactivate Ca(2+)-dependent exocytosis is based on its stimulatory effect on protein kinase C activity. As a result, the 14-3-3 family can be considered 'a multifunctional regulator of cell signalling processes mediated by two types of Ca(2+)-dependent protein kinase, protein kinase C and type II calmodulin-dependent pro- tein kinase.' /Note: The above text was probably used in updating comments included in all SwissProt DB records relevant to the human 14-3-3 proteins. The corresponding remark - (the protein) '.. STRONGLY ACTIVATES protein kinase C ..' - is probably appropriate in relation to the 14-3-3 ZETA protein. However, being included in descriptions all other 14-3-3 pro- teins and lacking additional clarifications, such a remark generates some misunderstanding since it contradicts to the main definition of the proteins as inhibiters of protein kinase C.\ %----------------------------------------------------------------------- <* > [LEFFERS H &:1993] (Inst Medical Biochemistry, Danish Centre for Hum Genome Research, Aarhus University) identified a family of abundant acidic human keratinocyte proteins with MM 30,000-31,100 in the master two-dimensional gel database of human keratinocyte proteins (isoelectric focussing sample spot proteins: #9109 - epithelial marker STRATIFIN, as well as #9124, #9125, #9126, and #9231). All these shared amino acid se- quences with each other and with some 14-3-3 proteins (inhibitors of the protein kinase C). Two-dimensional gel analysis cultured cells and fetal tissues showed that polypeptides comigrating with proteins 9124, 9125 and 9126 are ubiquitous and highly expressed in the brain whereas stratifin was expressed only in cultured epithelial cells and was most abundant in adult and fetal human tissues enriched in stratified squamous keratinis- ing epithelium. The authors cloned and sequenced cDNAs encoding members of this family. The identity of the sequenced peptides from stratifin with the amino acid sequence derived from the stratifin cDNA clone indi- cated that this cDNA encodes the given protein. The identity of clones 1054, HS1 and AS1 was less clear since none of their individual peptide sequences fits the protein sequences deduced from cDNAs. On the other hand, the polypeptides synthesized by clones 1054 and HS1 in the vaccinia expression system comigrated with proteins 9126 and 9124, that allows to suggest cell-type-specific expression of members of the protein family. Database searches indicated that clone HS1 corresponds to a human T-cell cDNA 14-3-3 clone (tau subtype) while clones 1054 and AS1 are strongly similar with the bovine 14-3-3 beta and eta sequences, respectively. The amino acid sequence of a short fragment also indicated that IEF SSP 9124 is probably the human homologue of bovine 14-3-3 gamma. %----------------------------------------------------------------------- <* > [ACCORDING TO SWANSON KD &:1993] (Dept of Biochemistry, Univ of Ten- nessee, Knoxville 37996), 14-3-3 proteins ACTIVATE tyrosine and trypto- phan hydroxylases, INHIBIT protein kinase C, and possess phospholipase A2 activity in vitro. The authors isolated a cDNA clone from a human fetal brain cDNA library and found its sequence highly similar to bovine 14-3-3 eta protein cDNA in both the translated and untranslated regions. The cloned cDNA hybridized with two mRNA species, 1.9 and 3.5 kb. North- ern blot experiments with poly(A)+RNA isolated from eight different hu- man tissues showed that these mRNAs are expressed in different tissues though the highest abundance of the eta mRNAs is seen in the brain. In addition, only the 1.9 kb mRNA is detected in the fetal brain. %----------------------------------------------------------------------- <* > [FU H &:1993] (Dept Microbiol and Mol Genetics, Harvard Med School, Boston, MA 02115) discovered that the eukaryotic host factor activating exoenzyme S of Pseudomonas aeruginosa is a member of the 14-3-3 protein family. The authors referred to the following facts: Exoenzyme S, ExoS, that has been implicated as a virulence factor of P.aeruginosa, catalyzes transfer of the ADP-ribose moiety of NAD+ to many eukaryotic cellular proteins; its preferred substrates include Ras and several other 21- to 25-kDa GTP-binding proteins; ExoS absolutely requires a ubiquitous eu- karyotic protein factor, termed FAS (Factor Activating exoS), for enzy- matic activity. The authors described the cloning and expression of a gene encoding FAS from a BOVINE brain cDNA library and showed that pur- ified recombinant FAS produced in Escherichia coli activates ExoS in a defined cell-free system. The putative amino acid sequence of FAS shows that the protein (245 aa residues; MW 27,743 Da) belongs to a highly conserved, widely distributed eukaryotic protein family, designated as 14-3-3 proteins. To date, various functions have been reported for members of this family, including phospholipase A2 activity and regulation of tyrosine/tryptophan hydroxylases and protein kinase C activities. Discovering of FAS as a 14-3-3 protein establishes one more function for this protein family - the activation of some exogenous ADP-ribosyltransferase. %----------------------------------------------------------------------- <* > [THE CRYSTAL STRUCTURES] of the HUMAN 14-3-3 TAU and BOVINE ZETA homodimers were recently published by Bing XIAO &:1995 (Division of Pro- tein Structure, National Inst for Med Res, The Ridgeway, Mill Hill, Lon- don NW7 1AA, UK) and Dong LIU &:1995 (Dana-Farber Cancer Inst and Dept Biol Chemistry and Mol Pharmacology, Harvard Medical School, 44 Binney Str, Boston, MA 02115), respectively. Both groups presented very similar data relating to the number and topology of alpha-helices in each of the monomers: nine antiparallel alpha-helicies are organized as two distinc- tive structural domains; when two monomers are bound to each other, the four structural domains form a particular structure - a "negatively charged channel" (Xiao B, 1995) or an "amphipathic groove" (Liu D, 1995). The authors also revealed that sixteen of the most conservative amino acids in different 14-3-3 isoforms form the base of this channel/groove. The latter fact allowed to suggest that this particular segment is res- ponsible for the binding of 14-3-3 proteins to several protein kinases and some other enzymes as well."


/Note: The following is aligned amino acid sequences of five known hu-
man proteins belonging to the 14-3-3 family. Conservative positions,
containing IDENTICAL or ISOFUNCTIONAL amino acids, are represented
by lower case letters while upper case letters represent variable
positions. For more information regarding this isofunctional amino
acid grouping, see Gindilis VM &:1994 (J Assist Reprod & Genet, 11,
N5, 244-269).
pep:ETA 1=mG-drEqllq rarlaeqaer yddmasamka vteLnEPlsn edrnllsvay=
pep:BETA 1=mTmdkselvq kaklaeqaer yddmaaamka vteqgHelsn eernllsvay=
pep:ZETA 1=--mdknelvq kaklaeqaer yddmaacmks vteqgaelsn eernllsvay=
pep:TAU 1=--mekteliq kaklaeqaer yddmatcmka vteqgaelsn eernllsvay=
pep:THETA 1=--meraSliq kaklaeqaer yedmaaFmkg AVeKgEelsC eernllsvay=
pep:ETA 50=knvvgarrss wrvissieqk tMAdgnekkL eKvkAyreki eKeletvcnd=
pep:BETA 51=knvvgarrss wrvissieqk t--eRnekkQ qmGkeyreki eaelqDicnd=
pep:ZETA 49=knvvgarrss wrvvssieqk t--egaekkQ qmAreyreki etelRDicnd=
pep:TAU 49=knvvggrrsa wrvissieqk t--dtsdkkL qLikdyrekv eselRsictT=
pep:THETA 49=knvvggQraa wrvlssieqk sNEegseekG PEvreyrekv etelqgvcDT=
pep:ETA 100=vlslldkfli KncndfqYes kvfylkmkgd yyrylaevas geKkNsvvea=
pep:BETA 99=vlElldkyli pnat--qpes kvfylkmkgd yfrylsevas gdnkQtTvSn=
pep:ZETA 97=vlsllekfli pnas--qaes kvfylkmkgd yyrylaevaa gddkkgivdQ=
pep:TAU 97=vlElldkyli anat--npes kvfylkmkgd yfrylaevac gddrkQTidn=
pep:THETA 99=vlglldSHli KeaGd--aes rvfylkmkgd yyrylaevat gddkkRiids=
pep:ETA 150=seaayKeafe iskeqmqpth pirlglalnf svfyyeiQna peqacllakQ=
pep:BETA 147=sqQayqeafe iskkemqpth pirlglalnf svfyyeilns pekacslakt=
pep:ZETA 145=sqQayqeafe iskkemqpth pirlglalnf svfyyeilns pekacslakt=
pep:TAU 145=sqgayqeafd iskkemqpth pirlglalnf svfyyeilnn peLactlakt=
pep:THETA 147=aRsayqeaMd iskkempptn pirlglalnf svfHyeiAns peeaIslakt=
pep:ETA 200=afddaiaeld tlnedsykds tlimqllrdn ltlwtsdQq- de--eageg-=
pep:BETA 197=afdeaiaeld tlneesykds tlimqllrdn ltlwtsenqg deg-dageg-=
pep:ZETA 195=afdeaiaeld tlseesykds tlimqllrdn ltlwtsdtqg dea-eagegg=
pep:TAU 195=afdeaiaeld tlnedsykds tlimqllrdn ltlwtsdsAg eec-daaega=
pep:THETA 197=TfdeaMadlH tlsedsykds tlimqllrdn ltlwtadnAg eeggeapq--=
pep:ETA 246=--n-=246\
pep:BETA 245=e-n-=246\
pep:ZETA 244=e-n-=245\
pep:TAU 244=e-n-=245\
pep:THETA 245=ePQS=248\"


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