Isoforms of 14‐3‐3 protein can form homo‐ and heterodimers in vivo and in vitro: implications for function as adapter proteins

Jones, David H.; Ley, Steven C.; Aitken, Alastair

doi:10.1016/0014-5793(95)00598-4

Cited by 239 publications

(213 citation statements)

References 19 publications

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“…Of note, we observed insolubilization of several 14‐3‐3 isoforms while S232 phosphorylation is specific to 14‐3‐3 θ . As 14‐3‐3 θ can heterodimerize with other isoforms38, 39, 40, these findings suggest that increased S232 phosphorylation of 14‐3‐3 θ may be sufficient to drive insolubilization of other isoforms through heterodimerization.…”

Section: Discussionmentioning

confidence: 89%

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

McFerrin

Chi

Cutter

et al. 2017

Ann Clin Transl Neurol

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ObjectiveThe highly conserved 14‐3‐3 proteins interact with key players involved in Parkinson's disease (PD) and other neurodegenerative disorders. We recently demonstrated that 14‐3‐3 phosphorylation is increased in PD models and that increased 14‐3‐3 phosphorylation reduces the neuroprotective effects of 14‐3‐3 proteins. Here, we investigated whether 14‐3‐3 phosphorylation is altered in postmortem brains from control, PD, Alzheimer's Disease (AD), Alzheimer's with Lewy Bodies (ADLB), Dementia with Lewy Bodies (DLB), and Progressive Supranuclear Palsy (PSP) subjects at three conserved sites: serine 58 (S58), serine 185 (S185), and serine 232 (S232).MethodsS58, S185, and S232 phosphorylation was measured by western blot analysis of Triton X‐100 soluble and insoluble fractions from postmortem temporal cortex.ResultsThe ratio of soluble phospho‐S232 to insoluble phospho‐S232 was reduced by 32%, 60%, 37%, and 52% in PD, AD, ADLB, and DLB, respectively. S185 and S58 phosphorylation were mildly elevated in the soluble fraction in DLB. We also noted a dramatic reduction in soluble pan 14‐3‐3 levels by ~35% in AD, ADLB, and DLB. Lower ratios of soluble to insoluble S232 phosphorylation (pointing to higher insoluble pS232) correlated with lower soluble pan 14‐3‐3 levels, suggesting that S232 phosphorylation may promote insolubilization of 14‐3‐3s. The phospho‐S232 ratio and soluble pan 14‐3‐3 levels correlated with clinical and pathological severity.InterpretationThese data reveal dysregulation of 14‐3‐3 proteins in neurodegeneration associated with Lewy body or Alzheimer pathology. S232 phosphorylation may drive insolubilization of 14‐3‐3s and thus contribute to the pathophysiology in neurodegenerative disorders associated with Lewy body or Alzheimer pathology.

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Section: Discussionmentioning

confidence: 89%

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

McFerrin

Chi

Cutter

et al. 2017

Ann Clin Transl Neurol

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“…Previous studies have shown that, apart from , several of the isoforms are able to form heterodimers (2,3). The presence of unique residues at the dimer interface provided a clear structural explanation for its homodimerization preference (38).…”

Section: Resultsmentioning

confidence: 96%

Structural basis for protein–protein interactions in the 14-3-3 protein family

Yang

Lee

Sobott

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

356

447

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The seven members of the human 14-3-3 protein family regulate a diverse range of cell signaling pathways by formation of proteinprotein complexes with signaling proteins that contain phosphorylated Ser͞Thr residues within specific sequence motifs. Previously, crystal structures of three 14-3-3 isoforms (zeta, sigma, and tau) have been reported, with structural data for two isoforms deposited in the Protein Data Bank (zeta and sigma). In this study, we provide structural detail for five 14-3-3 isoforms bound to ligands, providing structural coverage for all isoforms of a human protein family. A comparative structural analysis of the seven 14-3-3 proteins revealed specificity determinants for binding of phosphopeptides in a specific orientation, target domain interaction surfaces and flexible adaptation of 14-3-3 proteins through domain movements. Specifically, the structures of the beta isoform in its apo and peptide bound forms showed that its binding site can exhibit structural flexibility to facilitate binding of its protein and peptide partners. In addition, the complex of 14-3-3 beta with the exoenzyme S peptide displayed a secondary structural element in the 14-3-3 peptide binding groove. These results show that the 14-3-3 proteins are adaptable structures in which internal flexibility is likely to facilitate recognition and binding of their interaction partners.phosphorylation ͉ signaling

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“…The identification of coisolated proteins by mass spectrometry revealed interaction of Pik1p, Bmh1p/Bmh2p, and Frq1p ( Figure 1E), whereas other proteins represented common contaminants of the TAP procedure (Shevchenko et al, 2002). We conclude that the Pik1p-14-3-3 complex occurs in vivo and includes both Bmh1p and Bmh2p, which often function as a heterodimer (Jones et al, 1995).…”

Section: Pik1p Binds To the 14-3-3 Proteins Bmh1p And Bmh2pmentioning

confidence: 82%

Nucleocytoplasmic Shuttling of the Golgi Phosphatidylinositol 4-Kinase Pik1 Is Regulated by 14-3-3 Proteins and Coordinates Golgi Function with Cell Growth

Demmel

Beck

Klose

et al. 2008

MBoC

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The yeast phosphatidylinositol 4-kinase Pik1p is essential for proliferation, and it controls Golgi homeostasis and transport of newly synthesized proteins from this compartment. At the Golgi, phosphatidylinositol 4-phosphate recruits multiple cytosolic effectors involved in formation of post-Golgi transport vesicles. A second pool of catalytically active Pik1p localizes to the nucleus. The physiological significance and regulation of this dual localization of the lipid kinase remains unknown. Here, we show that Pik1p binds to the redundant 14-3-3 proteins Bmh1p and Bmh2p. We provide evidence that nucleocytoplasmic shuttling of Pik1p involves phosphorylation and that 14-3-3 proteins bind Pik1p in the cytoplasm. Nutrient deprivation results in relocation of Pik1p from the Golgi to the nucleus and increases the amount of Pik1p–14-3-3 complex, a process reversed upon restored nutrient supply. These data suggest a role of Pik1p nucleocytoplasmic shuttling in coordination of biosynthetic transport from the Golgi with nutrient signaling.

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Isoforms of 14‐3‐3 protein can form homo‐ and heterodimers in vivo and in vitro: implications for function as adapter proteins

Cited by 239 publications

References 19 publications

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

Dysregulation of 14‐3‐3 proteins in neurodegenerative diseases with Lewy body or Alzheimer pathology

Structural basis for protein–protein interactions in the 14-3-3 protein family

Nucleocytoplasmic Shuttling of the Golgi Phosphatidylinositol 4-Kinase Pik1 Is Regulated by 14-3-3 Proteins and Coordinates Golgi Function with Cell Growth

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