Differential Responses of the Backbone and Side-Chain Conformational Dynamics in FKBP12 upon Binding the Transition-State Analog FK506: Implications for Transition-State Stabilization and Target Protein Recognition

Brath, Ulrika; Akke, Mikael

doi:10.1016/j.jmb.2009.01.047

Cited by 34 publications

(60 citation statements)

References 77 publications

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“…3, C and D). Variation of conformational exchange line broadening with the square of the magnetic field strength is indicative of these conformational transitions occurring in the submillisecond time frame approaching the fast exchange limit (21), as had previously been reported for the ␤ 4 -␤ 5 loop in FKBP12 (43)(44)(45).…”

Section: Structural Analysis Of the Interface Between The ␤ 4 -␤supporting

confidence: 72%

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

LeMaster

Mustafi

Brecher

et al. 2015

Journal of Biological Chemistry

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Section: Structural Analysis Of the Interface Between The ␤ 4 -␤supporting

confidence: 72%

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

LeMaster

Mustafi

Brecher

et al. 2015

Journal of Biological Chemistry

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“…The binding of Vav1 SH2 to Syk linker B induces the phosphorylation of Vav1. Vav1 comprises seven domains, and conformational rearrangement in the secondary ␤-sheet region upon pYpY binding may be related to domain-domain interaction in the activation of Vav1 (5,40). This region has been reported to be an alternative site for phosphotyrosine-independent binding in other SH2 domains (16,29).…”

Section: Discussionmentioning

confidence: 99%

Two Closely Spaced Tyrosines Regulate NFAT Signaling in B Cells via Syk Association with Vav

Chen

Martin

Gorenstein

et al. 2011

Molecular and Cellular Biology

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Syk is a cytoplasmic protein tyrosine kinase that regulates cellular responses mediated by a variety of membrane receptors with intracellular signaling modules known as immunoreceptor tyrosine-based activation motifs (ITAMs) (23, 52). Examples of ITAM/Syk receptors include the B and T cell receptors for antigen, the immunoglobulin receptors FcεRI, Fc␥RI, and Fc␥RIIa, the activating NK cell receptors, and integrins. When these receptors are engaged, a pair of tyrosines within the ITAM become phosphorylated to create a docking site for Syk's N-terminal pair of SH2 domains. Syk binding to the ITAM leads to Syk activation and phosphorylation on several tyrosines to generate sites that participate in protein-protein interactions. Thus, activated Syk at the site of the clustered receptor participates in the formation of a signaling complex. This "signalosome" contains multiple effector proteins that include members of the Vav family of guanine nucleotide exchange factors (GEFs) (13,14).Among the three members of the Vav family, Vav1 is restricted largely to hematopoietic cells while Vav2 and Vav3 are more widely distributed (8,55,67,77). Vav proteins have both unique and redundant functions in the immune system, as a loss of Vav1 produces severe defects in T cell development and signaling, while the loss of more than one Vav family member is needed to produce similar defects in B cells (12,17,21,75,76). Vav proteins enhance many signaling pathways mediated by Syk-associated receptors, including the activation of phospholipase C-␥ (PLC-␥) and the mobilization of intracellular calcium, the activation of phosphoinositide 3-kinase (PI3K) and Akt, the activation of the Ras/Erk pathway, the promotion of cytoskeletal rearrangements, and the inside-out activation of integrins. While Vav proteins serve as GEFs for Rac/Rho family GTPases, they also act as scaffolds, a function that promotes the assembly of signaling complexes but does not require GEF activity (66).Syk associates with Vav family proteins and phosphorylates them on tyrosines that regulate their activity (13,43,50,53,59,69,74,75). This physical association occurs between the Vav SH2 domain and the Syk linker B region, which separates the tandem SH2 domains from the catalytic domain and contains phosphotyrosines 342 and 346 (based on the numbering system for murine Syk). Syk linker B interacts with multiple binding partners depending on which tyrosines in linker B are phosphorylated and the stoichiometry of this phosphorylation (23). As such, Syk linker B harbors the unusual site of two closely space tyrosines, which are recognized by a single SH2 domain of particular Syk binding partners. These interactions influence the ability of the kinase to couple ITAM-bearing receptors to the many different intracellular signaling pathways that are regulated following receptor engagement (23,52).Vav1 SH2 adopts the typical fold of an SH2 domain, including a central ␤-sheet flanked by two ␣-helices (Protein Data Bank [PDB] designation: 2CRH). The nonaromatic hydrophobic Ile r...

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“…However, the difference in 13 C relaxation data quality was vexing in light of the fact that the precisions of 15 N and 2 H relaxation parameters are the same for both the free enzyme and the drug-bound enzyme (data not shown), and all data sets were acquired from 1.5 mM samples that remained soluble throughout data collection and beyond. The previous observation that sidechain resonances near the FKBP12-FK506 interface 46 undergo chemical exchange leads us to hypothesize that aromatic resonances in the rapamycin complex are broadened for the same reason. This idea is supported by relaxation dispersion data for the FKBP12-rapamycin complex (see the text).…”

Section: Side-chain Dynamicsmentioning

confidence: 95%

“…The backbone 46 and side chains 47 of free FKBP12 were previously shown to undergo chemical exchange on the μ-ms timescale. While binding of FK506 completely quenches these motions in the backbone, many side chains remain flexible in the bound state.…”

Section: Addition Of Ligands Quenches Some-but Not All-fkbp12 Backbonmentioning

confidence: 99%

“…46,47 Because this method is very consumptive of spectrometer time, we sought to modulate the exchange kinetics to bring them into a regime suitable for Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion. By performing experiments at 5°C and using a transverse relaxation optimized spectroscopy (TROSY) CPMG pulse sequence, 48 we were able to robustly fit relaxation dispersion data to the fast-exchange approximation of the Richards-Carver equation.…”

Section: μ-Ms Dynamics In the Free Enzymementioning

confidence: 99%

See 1 more Smart Citation

Multi-Timescale Dynamics Study of FKBP12 Along the Rapamycin–mTOR Binding Coordinate

Sapienza

Mauldin

Lee

2011

Journal of Molecular Biology

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Differential Responses of the Backbone and Side-Chain Conformational Dynamics in FKBP12 upon Binding the Transition-State Analog FK506: Implications for Transition-State Stabilization and Target Protein Recognition

Cited by 34 publications

References 77 publications

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

Two Closely Spaced Tyrosines Regulate NFAT Signaling in B Cells via Syk Association with Vav

Multi-Timescale Dynamics Study of FKBP12 Along the Rapamycin–mTOR Binding Coordinate

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