Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: A comparison of the X-ray crystal structures of all human 14-3-3 isoforms

Gardino, Alexandra K.; Smerdon, Stephen J.; Yaffe, Michael B.

doi:10.1016/j.semcancer.2006.03.007

Cited by 257 publications

(317 citation statements)

References 84 publications

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“…Different degrees of cell death were observed following knockdown of each isoform, an unexpected finding, given a previous report that in Cos7 cells each isoform inhibits BAD-induced apoptosis to equal degrees [7]. The differences observed in cell death can be attributed to each isoform having unique interactomes, as structural analysis of the 14-3-3 family revealed a highly variable region between α-helices 8 and 9, which determines binding specificity [42]. This concept has been validated in screens of human 14-3-3 binding partners, which revealed common and unique protein × protein interactions among the tested isoforms [43].…”

Section: Discussionmentioning

confidence: 77%

14-3-3 proteins are essential signalling hubs for beta cell survival

2013

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Section: Discussionmentioning

confidence: 77%

14-3-3 proteins are essential signalling hubs for beta cell survival

2013

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“…The overall structural features of the 14-3-3 protein family members were recently reviewed (41), and thus only a brief description is provided here. The determined 14-3-3 crystal structures were all homodimers.…”

Section: Resultsmentioning

confidence: 99%

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.

362

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 phosphopeptide was bound to the well-characterized binding pocket between ␣-helices E and F of each 14-3-3 molecules. 35 The main electrostatic interactions were between Thr758 phosphate group of the ␤2 peptide and 14-3-3 Arg residues 56 and 127, which form a typical basic batch in the binding site ( Figures 4A,5). A hydrogen bond was observed between the phosphate group and Tyr128 of 14-3-3 ( Figure 5A,B).…”

Section: Structures Of Filamin/␤2 and 14-3-3/phospho-␤2 Complexesmentioning

confidence: 99%

“…by guest www.bloodjournal.org From phosphopeptide/14-3-3 structures where the phosphate group has been shown to be the key determinant for binding. 35 …”

Section: Structures Of Filamin/␤2 and 14-3-3/phospho-␤2 Complexesmentioning

confidence: 99%

β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding

Takala

Nurminen

Nurmi³

et al. 2008

Blood

149

235

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Leukocyte integrins of the ␤2 family are essential for immune cell-cell adhesion. In activated cells, ␤2 integrins are phosphorylated on the cytoplasmic Thr758, leading to 14-3-3 protein recruitment to the ␤2 integrin. The mutation of this phosphorylation site impairs cell adhesion, actin reorganization, and cell spreading. Thr758 is contained in a Thr triplet of ␤2 that also mediates binding to filamin. Here, we investigated the binding of filamin, talin, and 14-3-3 proteins to phosphorylated and unphosphorylated ␤2 integrins by biochemical methods and x-ray crystallography. 14-3-3 proteins bound only to the phosphorylated integrin cytoplasmic peptide, with a high affinity (K d , 261 nM), whereas filamin bound only the unphosphorylated integrin cytoplasmic peptide (K d , 0.5 mM). Phosphorylation did not regulate talin binding to ␤2 directly, but 14-3-3 was able to outcompete talin for the binding to phosphorylated ␤2 integrin. X-ray crystallographic data clearly IntroductionIntegrins are heterodimeric plasma membrane receptors that mediate binding to the extracellular matrix and to ligands present on the surface of other cells. Their function is tightly regulated; they bind ligands only after activation. Modulation of integrin activity occurs through tightly regulated interactions between cytoplasmic molecules and integrin intracellular tails. Factors binding to integrin cytoplasmic domains regulating integrin adhesiveness include the cytoskeletal proteins talin 1,2 and filamin, 3 and the 14-3-3 proteins, which are molecular adaptors that bind to phosphorylated serine or threonine (pSer/ pThr) containing polypeptide sequences. 4 The ␤2 integrins are expressed exclusively on leukocytes and bind ICAM molecules on other leukocytes and endothelial cells after cell activation. 5,6 Talin binds to ␤2 integrins in vitro and in cells and is involved in activating the ␤2 integrins, resulting in binding to ICAMs. 1,4,[7][8][9] The ␤2 integrin polypeptide chain is phosphorylated on the intracellular domain on several residues after cell stimulation with various agents. 10 Thr758 is a physiologically important amino acid residue in the ␤2 cytoplasmic tail, and becomes phosphorylated after T-cell stimulation with T-cell receptor (TCR) antibodies or with phorbol esters. [11][12][13] After its phosphorylation, ␤2 binds to 14-3-3 proteins both in vitro and in cells. 4 Blocking of this interaction with a ␤2 Thr758 to Ala mutation, or by expression of constructs that bind to 14-3-3 proteins and block their interactions with target proteins, leads to abrogation of actin cytoskeleton rearrangements, cell spreading, and adhesion to ICAM ligands. 4 ␤2-Thr758 phosphorylation leads to the activation of the actin cytoskeleton modulators, Rac1/Cdc42, in cells. 13 The region in the ␤2 cytoplasmic tail that binds 14-3-3 proteins has been reported to interact with filamin in other integrins, 14 and for the strong filamin-binder ␤7 integrin, phosphorylation mimicking substitutions of 3 threonine residues (TTT) reduces filamin affinity. 3 Fi...

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Structural determinants of 14-3-3 binding specificities and regulation of subcellular localization of 14-3-3-ligand complexes: A comparison of the X-ray crystal structures of all human 14-3-3 isoforms

Cited by 257 publications

References 84 publications

14-3-3 proteins are essential signalling hubs for beta cell survival

14-3-3 proteins are essential signalling hubs for beta cell survival

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

β2 integrin phosphorylation on Thr758 acts as a molecular switch to regulate 14-3-3 and filamin binding

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