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| image = PDB 1ib1 EBI.jpg
| image = PDB 1ib1 EBI.jpg
| width =
| width =
| caption = Crystal structure of the 14-3-3 zeta:serotonin N-acetyltransferase complex.<ref>{{Cite journal | author = T. Obsil | author2 = R. Ghirlando | author3 = D. C. Klein| author4 = S. Ganguly | author5 = F. Dyda | last-author-amp = yes | title = Crystal structure of the 14-3-3zeta:serotonin N-acetyltransferase complex. a role for scaffolding in enzyme regulation
| caption = Crystal structure of the 14-3-3 zeta:serotonin N-acetyltransferase complex.<ref>{{cite journal | vauthors = Obsil T, Ghirlando R, Klein DC, Ganguly S, Dyda F | title = Crystal structure of the 14-3-3zeta:serotonin N-acetyltransferase complex. a role for scaffolding in enzyme regulation | journal = Cell | volume = 105 | issue = 2 | pages = 257–67 | date = April 2001 | pmid = 11336675 | doi = 10.1016/S0092-8674(01)00316-6 | last-author-amp = yes }}</ref>
| journal = [[Cell (journal)|Cell]] | volume = 105 | issue = 2 | pages = 257–267 |date=April 2001 | pmid = 11336675 | doi=10.1016/S0092-8674(01)00316-6}}</ref>
| Pfam = PF00244
| Pfam = PF00244
| Pfam_clan =
| Pfam_clan =
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'''14-3-3 proteins''' are a family of conserved regulatory [[molecule]]s that are expressed in all [[eukaryote|eukaryotic]] cells. 14-3-3 [[protein]]s have the ability to bind a multitude of functionally diverse [[signal transduction|signaling proteins]], including [[kinase]]s, [[phosphatase]]s, and [[transmembrane receptor]]s. More than 200 signaling proteins have been reported as 14-3-3 ligands.
'''14-3-3 proteins''' are a family of conserved regulatory [[molecule]]s that are expressed in all [[eukaryote|eukaryotic]] cells. 14-3-3 [[protein]]s have the ability to bind a multitude of functionally diverse [[signal transduction|signaling proteins]], including [[kinase]]s, [[phosphatase]]s, and [[transmembrane receptor]]s. More than 200 signaling proteins have been reported as 14-3-3 ligands.


Elevated amounts of 14-3-3 proteins are found in the [[cerebrospinal fluid]] of patients with [[Creutzfeldt–Jakob disease]].<ref name="pmid10548598">{{cite journal | vauthors = Takahashi H, Iwata T, Kitagawa Y, Takahashi RH, Sato Y, Wakabayashi H, Takashima M, Kido H, Nagashima K, Kenney K, Gibbs CJ, Kurata T | title = Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt–Jakob disease | journal = Clinical and Diagnostic Laboratory Immunology | volume = 6 | issue = 6 | pages = 983–5 | date = Nov 1999 | pmid = 10548598 | pmc = 95810 | doi = }}</ref>
Elevated amounts of 14-3-3 proteins are found in the [[cerebrospinal fluid]] of patients with [[Creutzfeldt–Jakob disease]].<ref name="pmid10548598">{{cite journal | vauthors = Takahashi H, Iwata T, Kitagawa Y, Takahashi RH, Sato Y, Wakabayashi H, Takashima M, Kido H, Nagashima K, Kenney K, Gibbs CJ, Kurata T | title = Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt-Jakob disease | journal = Clinical and Diagnostic Laboratory Immunology | volume = 6 | issue = 6 | pages = 983–5 | date = November 1999 | pmid = 10548598 | pmc = 95810 | doi = }}</ref>


[[File:14-3-3dimer.png|thumb|right|Molecular structure of a 14-3-3 protein dimer bound to a peptide.]]
[[File:14-3-3dimer.png|thumb|right|Molecular structure of a 14-3-3 protein dimer bound to a peptide.]]
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There are seven genes that encode seven distinct 14-3-3 proteins in most mammals (See ''Human genes'' below) and 13-15 genes in many higher plants, though typically in fungi they are present only in pairs. [[Protist]]s have at least one. [[Eukaryote]]s can tolerate the loss of a single 14-3-3 gene if multiple genes are expressed, however deletion of all 14-3-3s (as experimentally determined in yeast) results in death.{{citation needed|date=October 2016}}
There are seven genes that encode seven distinct 14-3-3 proteins in most mammals (See ''Human genes'' below) and 13-15 genes in many higher plants, though typically in fungi they are present only in pairs. [[Protist]]s have at least one. [[Eukaryote]]s can tolerate the loss of a single 14-3-3 gene if multiple genes are expressed, however deletion of all 14-3-3s (as experimentally determined in yeast) results in death.{{citation needed|date=October 2016}}


14-3-3 proteins are structurally similar to the [[Tetratricopeptide|Tetratrico Peptide Repeat (TPR)]] superfamily, which generally have 9 or 10 [[alpha helix|alpha helices]], and usually form homo- and/or hetero-dimer interactions along their amino-termini helices. These proteins contain a number of known common modification domains, including regions for divalent [[cation]] interaction, [[phosphorylation]] & [[acetylation]], and proteolytic cleavage, among others established and predicted.<ref>{{cite journal |last1=Bridges |first1=D. |last2=Moorhead |first2=G. B. G. |title=14-3-3 Proteins: A Number of Functions for a Numbered Protein |journal=Science Signaling |date=2 August 2005 |volume=2005 |issue=296 |pages=re10–re10 |doi=10.1126/stke.2962005re10}}</ref>
14-3-3 proteins are structurally similar to the [[Tetratricopeptide|Tetratrico Peptide Repeat (TPR)]] superfamily, which generally have 9 or 10 [[alpha helix|alpha helices]], and usually form homo- and/or hetero-dimer interactions along their amino-termini helices. These proteins contain a number of known common modification domains, including regions for divalent [[cation]] interaction, [[phosphorylation]] & [[acetylation]], and proteolytic cleavage, among others established and predicted.<ref>{{cite journal | vauthors = Bridges D, Moorhead GB | title = 14-3-3 proteins: a number of functions for a numbered protein | journal = Science's STKE | volume = 2005 | issue = 296 | pages = re10 | date = August 2005 | pmid = 16091624 | doi = 10.1126/stke.2962005re10 }}</ref>


14-3-3 binds to peptides. There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or [[threonine]] residue, although binding to non-phosphorylated [[ligands]] has also been reported. This interaction occurs along a so-called binding groove or cleft that is [[amphipathic]] in nature. To date, the crystal structures of six classes of these proteins have been resolved and deposited in the public domain.{{citation needed|date=October 2016}}
14-3-3 binds to peptides. There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or [[threonine]] residue, although binding to non-phosphorylated [[ligands]] has also been reported. This interaction occurs along a so-called binding groove or cleft that is [[amphipathic]] in nature. To date, the crystal structures of six classes of these proteins have been resolved and deposited in the public domain.{{citation needed|date=October 2016}}


{|class=wikitable
{|class=wikitable
|+ style="font-family: sans-serif"| 14-3-3 recognition motifs<ref>{{cite web |title=ELM search: "14-3-3" |url=http://elm.eu.org/combined_search?query=14-3-3 |website=Eukaryotic Linear Motif resource |accessdate=16 May 2019}}</ref>
|+ style="font-family: sans-serif"| 14-3-3 recognition motifs<ref>{{cite web |title=ELM search: "14-3-3" |url=http://elm.eu.org/combined_search?query=14-3-3 |website=Eukaryotic Linear Motif resource |access-date=16 May 2019}}</ref>
! Canonical
! Canonical
|
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|}


===Function===
=== Function ===
14-3-3 proteins play an isoform-specific role in [[class switch recombination]]. They are believed to interact with the protein [[Activation-Induced (Cytidine) Deaminase]] in mediating class switch recombination.{{citation needed|date=October 2016}}
14-3-3 proteins play an isoform-specific role in [[class switch recombination]]. They are believed to interact with the protein [[Activation-Induced (Cytidine) Deaminase]] in mediating class switch recombination.{{citation needed|date=October 2016}}


Phosphorylation of [[Cdc25C]] by [[CDS1]] and [[CHEK1]] creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.<ref name="pmid18059525">{{cite journal | vauthors = Cann KL, Hicks GG | title = Regulation of the cellular DNA double-strand break response | journal = Biochemistry and Cell Biology | volume = 85 | issue = 6 | pages = 663–74 | date = Dec 2007 | pmid = 18059525 | pmc = | doi = 10.1139/O07-135 | url = https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18059525 }}</ref>
Phosphorylation of [[Cdc25C]] by [[CDS1]] and [[CHEK1]] creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.<ref name="pmid18059525">{{cite journal | vauthors = Cann KL, Hicks GG | title = Regulation of the cellular DNA double-strand break response | journal = Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire | volume = 85 | issue = 6 | pages = 663–74 | date = December 2007 | pmid = 18059525 | pmc = | doi = 10.1139/O07-135 | url = https://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18059525 }}</ref>


The eta isoform is reported to be a biomarker (in [[synovial fluid]]) for [[rheumatoid arthritis]].<ref>[https://www.ncbi.nlm.nih.gov/pubmed/?term=17611984 Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation.]</ref>
The eta isoform is reported to be a biomarker (in [[synovial fluid]]) for [[rheumatoid arthritis]].<ref>[https://www.ncbi.nlm.nih.gov/pubmed/?term=17611984 Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation.]</ref>
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*'''[[Cdc25]]'''
*'''[[Cdc25]]'''
*'''[[Akt]]'''
*'''[[Akt]]'''
*'''[[SOS1]]'''<ref>{{Cite journal|title = RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation|last = Saha|first = Madhurima|date = 2012|journal = Biochemical Journal|doi = 10.1042/BJ20120938|pmid = 22827337|first2 = Audrey|last2 = Carriere|first3 = Mujeeburahiman|last3 = Cheerathodi|first4 = Xiaocui|last4 = Zhang|first5 = Geneviève|last5 = Lavoie|first6 = John|last6 = Rush|first7 = Philippe|last7 = Roux|first8 = Bryan|last8 = Ballif|pmc=4198020|volume=447|pages=159–66}}</ref> – see [[Ribosomal s6 kinase|RSK]]
*'''[[SOS1]]'''<ref>{{cite journal | vauthors = Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA | title = RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation | journal = The Biochemical Journal | volume = 447 | issue = 1 | pages = 159–66 | date = October 2012 | pmid = 22827337 | pmc = 4198020 | doi = 10.1042/BJ20120938 }}</ref> – see [[Ribosomal s6 kinase|RSK]]


==Human genes==
==Human genes==
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A phylogenetic analysis of 27 plant species clustered the 14-3-3 proteins into four groups.
A phylogenetic analysis of 27 plant species clustered the 14-3-3 proteins into four groups.


14-3-3 proteins activate the auto-inhibited plasma membrane [[P-type ATPase|P-type H<sup>+</sup> ATPases]]. They bind the ATPases' C-terminus at a conserved threonine.<ref>{{cite journal | vauthors = Jahn TP, Schulz A, Taipalensuu J, Palmgren MG | title = Post-translational modification of plant plasma membrane H(+)-ATPase as a requirement for functional complementation of a yeast transport mutant | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 6353–6358 | date = Feb 2002 | pmid = 11744700 | doi = 10.1074/jbc.M109637200 }}</ref>
14-3-3 proteins activate the auto-inhibited plasma membrane [[P-type ATPase|P-type H<sup>+</sup> ATPases]]. They bind the ATPases' C-terminus at a conserved threonine.<ref>{{cite journal | vauthors = Jahn TP, Schulz A, Taipalensuu J, Palmgren MG | title = Post-translational modification of plant plasma membrane H(+)-ATPase as a requirement for functional complementation of a yeast transport mutant | journal = The Journal of Biological Chemistry | volume = 277 | issue = 8 | pages = 6353–8 | date = February 2002 | pmid = 11744700 | doi = 10.1074/jbc.M109637200 }}</ref>


== References ==
== References ==
Line 89: Line 88:
== Further reading ==
== Further reading ==
* {{cite book |vauthors=Moore BW, Perez VJ |title=Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Inc., The Marine Biological Laboratory, Woods Hole, MA |editor=FD Carlson |pages=343–359 |year=1967}}
* {{cite book |vauthors=Moore BW, Perez VJ |title=Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Inc., The Marine Biological Laboratory, Woods Hole, MA |editor=FD Carlson |pages=343–359 |year=1967}}
* {{cite journal | vauthors = Mhawech P | title = 14-3-3 proteins--an update | journal = Cell Research | volume = 15 | issue = 4 | pages = 228–236 | date = Apr 2005 | pmid = 15857577 | doi = 10.1038/sj.cr.7290291 }}
* {{cite journal | vauthors = Mhawech P | title = 14-3-3 proteins--an update | journal = Cell Research | volume = 15 | issue = 4 | pages = 228–36 | date = April 2005 | pmid = 15857577 | doi = 10.1038/sj.cr.7290291 }}
* {{cite journal | vauthors = Steinacker P, Aitken A, Otto M | title = 14-3-3 proteins in neurodegeneration | journal = Seminars in Cell & Developmental Biology | volume = 22 | issue = 7 | pages = 696–704 | date = Sep 2011 | pmid = 21920445 | doi = 10.1016/j.semcdb.2011.08.005 }}
* {{cite journal | vauthors = Steinacker P, Aitken A, Otto M | title = 14-3-3 proteins in neurodegeneration | journal = Seminars in Cell & Developmental Biology | volume = 22 | issue = 7 | pages = 696–704 | date = September 2011 | pmid = 21920445 | doi = 10.1016/j.semcdb.2011.08.005 }}


== External links ==
== External links ==

Revision as of 09:59, 18 May 2019

14-3-3
Crystal structure of the 14-3-3 zeta:serotonin N-acetyltransferase complex.[1]
Identifiers
Symbol14-3-3
PfamPF00244
InterProIPR000308
SMART14_3_3
PROSITEPDOC00633
SCOP21a4o / SCOPe / SUPFAM
Available protein structures:
Pfam  structures / ECOD  
PDBRCSB PDB; PDBe; PDBj
PDBsumstructure summary

14-3-3 proteins are a family of conserved regulatory molecules that are expressed in all eukaryotic cells. 14-3-3 proteins have the ability to bind a multitude of functionally diverse signaling proteins, including kinases, phosphatases, and transmembrane receptors. More than 200 signaling proteins have been reported as 14-3-3 ligands.

Elevated amounts of 14-3-3 proteins are found in the cerebrospinal fluid of patients with Creutzfeldt–Jakob disease.[2]

Molecular structure of a 14-3-3 protein dimer bound to a peptide.

Properties

There are seven genes that encode seven distinct 14-3-3 proteins in most mammals (See Human genes below) and 13-15 genes in many higher plants, though typically in fungi they are present only in pairs. Protists have at least one. Eukaryotes can tolerate the loss of a single 14-3-3 gene if multiple genes are expressed, however deletion of all 14-3-3s (as experimentally determined in yeast) results in death.[citation needed]

14-3-3 proteins are structurally similar to the Tetratrico Peptide Repeat (TPR) superfamily, which generally have 9 or 10 alpha helices, and usually form homo- and/or hetero-dimer interactions along their amino-termini helices. These proteins contain a number of known common modification domains, including regions for divalent cation interaction, phosphorylation & acetylation, and proteolytic cleavage, among others established and predicted.[3]

14-3-3 binds to peptides. There are common recognition motifs for 14-3-3 proteins that contain a phosphorylated serine or threonine residue, although binding to non-phosphorylated ligands has also been reported. This interaction occurs along a so-called binding groove or cleft that is amphipathic in nature. To date, the crystal structures of six classes of these proteins have been resolved and deposited in the public domain.[citation needed]

14-3-3 recognition motifs[4]
Canonical 
R[^DE]{0,2}[^DEPG]([ST])(([FWYLMV].)
                        |([^PRIKGN]P)
                        |([^PRIKGN].{2,4}[VILMFWYP]))
C-terminal 
R[^DE]{0,2}[^DEPG]([ST])[^P]{0,1}$
Non-phos (ATP) 
IR[^P][^P]N[^P][^P]WR[^P]W[YFH][ITML][^P]Y[IVL]
All entrys are in regular expression format. Newlines are added in "or" cases for readability. Phosphorylation sites are in bold.

Function

14-3-3 proteins play an isoform-specific role in class switch recombination. They are believed to interact with the protein Activation-Induced (Cytidine) Deaminase in mediating class switch recombination.[citation needed]

Phosphorylation of Cdc25C by CDS1 and CHEK1 creates a binding site for the 14-3-3 family of phosphoserine binding proteins. Binding of 14-3-3 has little effect on Cdc25C activity, and it is believed that 14-3-3 regulates Cdc25C by sequestering it to the cytoplasm, thereby preventing the interactions with CycB-Cdk1 that are localized to the nucleus at the G2/M transition.[5]

The eta isoform is reported to be a biomarker (in synovial fluid) for rheumatoid arthritis.[6]

14-3-3 regulating cell-signalling

Human genes

The 14-3-3 proteins alpha and delta (YWHAA and YWHAD) are phosphorylated forms of YWHAB and YWHAZ, respectively.

In plants

Presence of large gene families of 14-3-3 proteins in the Viridiplantae kingdom reflects their essential role in plant physiology. A phylogenetic analysis of 27 plant species clustered the 14-3-3 proteins into four groups.

14-3-3 proteins activate the auto-inhibited plasma membrane P-type H+ ATPases. They bind the ATPases' C-terminus at a conserved threonine.[8]

References

  1. ^ Obsil T, Ghirlando R, Klein DC, Ganguly S, Dyda F (April 2001). "Crystal structure of the 14-3-3zeta:serotonin N-acetyltransferase complex. a role for scaffolding in enzyme regulation". Cell. 105 (2): 257–67. doi:10.1016/S0092-8674(01)00316-6. PMID 11336675. {{cite journal}}: Unknown parameter |last-author-amp= ignored (|name-list-style= suggested) (help)
  2. ^ Takahashi H, Iwata T, Kitagawa Y, Takahashi RH, Sato Y, Wakabayashi H, Takashima M, Kido H, Nagashima K, Kenney K, Gibbs CJ, Kurata T (November 1999). "Increased levels of epsilon and gamma isoforms of 14-3-3 proteins in cerebrospinal fluid in patients with Creutzfeldt-Jakob disease". Clinical and Diagnostic Laboratory Immunology. 6 (6): 983–5. PMC 95810. PMID 10548598.
  3. ^ Bridges D, Moorhead GB (August 2005). "14-3-3 proteins: a number of functions for a numbered protein". Science's STKE. 2005 (296): re10. doi:10.1126/stke.2962005re10. PMID 16091624.
  4. ^ "ELM search: "14-3-3"". Eukaryotic Linear Motif resource. Retrieved 16 May 2019.
  5. ^ Cann KL, Hicks GG (December 2007). "Regulation of the cellular DNA double-strand break response". Biochemistry and Cell Biology = Biochimie et Biologie Cellulaire. 85 (6): 663–74. doi:10.1139/O07-135. PMID 18059525.
  6. ^ Detection of high levels of 2 specific isoforms of 14-3-3 proteins in synovial fluid from patients with joint inflammation.
  7. ^ Saha M, Carriere A, Cheerathodi M, Zhang X, Lavoie G, Rush J, Roux PP, Ballif BA (October 2012). "RSK phosphorylates SOS1 creating 14-3-3-docking sites and negatively regulating MAPK activation". The Biochemical Journal. 447 (1): 159–66. doi:10.1042/BJ20120938. PMC 4198020. PMID 22827337.
  8. ^ Jahn TP, Schulz A, Taipalensuu J, Palmgren MG (February 2002). "Post-translational modification of plant plasma membrane H(+)-ATPase as a requirement for functional complementation of a yeast transport mutant". The Journal of Biological Chemistry. 277 (8): 6353–8. doi:10.1074/jbc.M109637200. PMID 11744700.{{cite journal}}: CS1 maint: unflagged free DOI (link)

Further reading

  • Moore BW, Perez VJ (1967). FD Carlson (ed.). Physiological and Biochemical Aspects of Nervous Integration. Prentice-Hall, Inc., The Marine Biological Laboratory, Woods Hole, MA. pp. 343–359.
  • Mhawech P (April 2005). "14-3-3 proteins--an update". Cell Research. 15 (4): 228–36. doi:10.1038/sj.cr.7290291. PMID 15857577.
  • Steinacker P, Aitken A, Otto M (September 2011). "14-3-3 proteins in neurodegeneration". Seminars in Cell & Developmental Biology. 22 (7): 696–704. doi:10.1016/j.semcdb.2011.08.005. PMID 21920445.

External links

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