Regulation of αA- and αB-crystallins via phosphorylation in cellular homeostasis

Thornell, Erin; Aquilina, Andrew

doi:10.1007/s00018-015-1996-x

Cited by 29 publications

(23 citation statements)

References 117 publications

(207 reference statements)

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“…Upon stress, the presence of unfolding substrate proteins that interact with these binding sites induces a shift in the equilibrium of the sHsp ensemble toward the more active species (87,92,139). Regulating sHsp activity by phosphorylation or more generally by posttranslational modifications is especially found in eukaryotes (34,35,(145)(146)(147)(148)(149)(150). The most extensively studied example in this respect is human Hsp27 (HSPB1), which possesses three phosphorylation sites (Ser-15, Ser-78, and Ser-82) within its NTR that are modified via a for mitogen-activated protein kinase cascade (147,151,152).…”

Section: Substrate Recognitionmentioning

confidence: 99%

Small heat shock proteins: Simplicity meets complexity

Haslbeck

Weinkauf

Büchner

2019

Journal of Biological Chemistry

237

218

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Edited by Norma M. Allewell Small heat shock proteins (sHsps) are a ubiquitous and ancient family of ATP-independent molecular chaperones. A key characteristic of sHsps is that they exist in ensembles of iso-energetic oligomeric species differing in size. This property arises from a unique mode of assembly involving several parts of the subunits in a flexible manner. Current evidence suggests that smaller oligomers are more active chaperones. Thus, a shift in the equilibrium of the sHsp ensemble allows regulating the chaperone activity. Different mechanisms have been identified that reversibly change the oligomer equilibrium. The promiscuous interaction with non-native proteins generates complexes that can form aggregate-like structures from which native proteins are restored by ATP-dependent chaperones such as Hsp70 family members. In recent years, this basic paradigm has been expanded, and new roles and new cofactors, as well as variations in structure and regulation of sHsps, have emerged. This work was supported by Deutsche Forschungsgemeinschaft Grant SFB 1035. This is the fifth article in the JBC Reviews series "Molecular chaperones and protein quality control." The authors declare that they have no conflicts of interest with the contents of this article.

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Section: Substrate Recognitionmentioning

confidence: 99%

Small heat shock proteins: Simplicity meets complexity

Haslbeck

Weinkauf

Büchner

2019

Journal of Biological Chemistry

237

218

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“…This interaction may play a role during IF assembly since sHSP influence IF solubility . Although sHSP are ATP‐independent chaperones, they are regulated by ATP‐dependent PTM‐like phosphorylation , and sHSP cooperate with ATP‐dependent chaperones .…”

Section: Unlike Mature If Vimentin Filament Precursors Actively Exchmentioning

confidence: 99%

Intermediate filament dynamics: What we can see now and why it matters

Ahrends

Hookway²,

Gelfand³

2016

BioEssays

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The mechanical properties of vertebrate cells are largely defined by the system of intermediate filaments (IF). As part of a dense network, IF polymers are constantly rearranged and relocalized in the cell to fulfill their duty as cells change shape, migrate, or divide. With the development of new imaging technologies, such as photo-convertible proteins and super-resolution microscopy, a new appreciation for the complexity of IF dynamics has emerged. This review highlights new findings about the transport of IF, the remodeling of filaments by a process of severing and re-annealing, and the subunit exchange that occurs between filament precursors and a soluble pool of IF. We will also discuss the unique dynamic features of the keratin IF network. Finally, we will speculate about how the dynamic properties of IF are related to their functions.

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“…Looking at the results of the αB-Crystallin case study, we can infer a great influence of Ser59 phosphorylation on chain B for the regulation of the protein multimerization. The key role of phosphorylation for the αB-Crystallin structure was widely demonstrated [ 16 , 19 , 20 ], as also the connection between phosphorylation level and chaperone activity [ 38 ]. In particular, phosphorylation of Ser59 has a role in ischemic stress, in the expression and regulation of cytoprotective proteins, like Bcl2 [ 39 ], and in the ubiquitin–proteasome system [ 40 ].…”

Section: Resultsmentioning

confidence: 99%

A novel molecular dynamics approach to evaluate the effect of phosphorylation on multimeric protein interface: the αB-Crystallin case study

et al. 2016

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BackgroundPhosphorylation is one of the most important post-translational modifications (PTM) employed by cells to regulate several cellular processes. Studying the effects of phosphorylations on protein structures allows to investigate the modulation mechanisms of several proteins including chaperones, like the small HSPs, which display different multimeric structures according to the phosphorylation of a few serine residues. In this context, the proposed study is aimed at finding a method to correlate different PTM patterns (in particular phosphorylations at the monomers interface of multimeric complexes) with the dynamic behaviour of the complex, using physicochemical parameters derived from molecular dynamics simulations in the timescale of nanoseconds.ResultsWe have developed a methodology relying on computing nine physicochemical parameters, derived from the analysis of short MD simulations, and combined with N identifiers that characterize the PTMs of the analysed protein. The nine general parameters were validated on three proteins, with known post-translational modified conformation and unmodified conformation. Then, we applied this approach to the case study of αB-Crystallin, a chaperone which multimeric state (up to 40 units) is supposed to be controlled by phosphorylation of Ser45 and Ser59. Phosphorylation of serines at the dimer interface induces the release of hexamers, the active state of αB-Crystallin. 30 ns of MD simulation were obtained for each possible combination of dimer phosphorylation state and average values of structural, dynamic, energetic and functional features were calculated on the equilibrated portion of the trajectories. Principal Component Analysis was applied to the parameters and the first five Principal Components, which summed up to 84 % of the total variance, were finally considered.ConclusionsThe validation of this approach on multimeric proteins, which structures were known both modified and unmodified, allowed us to propose a new approach that can be used to predict the impact of PTM patterns in multi-modified proteins using data collected from short molecular dynamics simulations. Analysis on the αB-Crystallin case study clusters together all-P dimers with all-P hexamers and no-P dimer with no-P hexamer and results suggest a great influence of Ser59 phosphorylation on chain B.

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Regulation of αA- and αB-crystallins via phosphorylation in cellular homeostasis

Cited by 29 publications

References 117 publications

Small heat shock proteins: Simplicity meets complexity

Small heat shock proteins: Simplicity meets complexity

Intermediate filament dynamics: What we can see now and why it matters

A novel molecular dynamics approach to evaluate the effect of phosphorylation on multimeric protein interface: the αB-Crystallin case study

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