Conformational Dynamics and Functional Implications of Phosphorylated β-Arrestins

Kang, Hyunook; Yang, Han-Sol; Ki, Ah Young; Ko, Seung-Bum; Kim, Kwon Woo; Shim, Chang Yong; Kim, Kiae; Chung, Ka Young

doi:10.1016/j.str.2019.12.008

Cited by 9 publications

(12 citation statements)

References 43 publications

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“…There are several crystallographic structures of both arrestin-2 and arrestin-3. These structures include apo arrestin [40, 44, 47, 50, 51], as well as arrestin bound to clathrin [43], inositol hexaphosphate ( IP6 ) [39, 46], activating peptides [41, 55, 56], and GPCRs [42, 48, 49]. They form three distinct structural clusters, as shown by Figure 3: an apo cluster with the C-tail domain bound to the N-domain, and two distinct active conformations representing the C-tail unbinding and the N-domain and C-domain rotating with respect to each other.…”

Section: Resultsmentioning

confidence: 99%

“…We analyzed a total 26 X-ray structures. Of these, 9 were apo structures, 1 was clathrin-bound, 2 were inositol-6phosphate (IP6) activated structures, 4 were GPCR-activated arrestin structures, and 10 were peptide-activated (Table 1) [39][40][41][42][43][44][45][46][47][48][49][50][51]. Nineteen (19) of the structures were arrestin-2, while 7 were arrestin-3.…”

Section: X-ray Structure Selection and Analysismentioning

confidence: 99%

“…However, the precise nature of these changes, particularly in dynamics, and their relation to activity remains elusive. This has been the focus of numerous crystallographic studies [39][40][41][42][43][44][46][47][48][49][50][51]. There also have been several HX-MS and electron paramagnetic resonance (EPR) studies that probe the solution structure and dynamics of arrestin and how those dynamics change upon activation [6,22,44,[57][58][59][60][61][62].…”

Section: Comparison To Experimental Studiesmentioning

confidence: 99%

“…This has been the focus of numerous crystallographic studies [39][40][41][42][43][44][46][47][48][49][50][51]. There also have been several HX-MS and electron paramagnetic resonance (EPR) studies that probe the solution structure and dynamics of arrestin and how those dynamics change upon activation [6,22,44,[57][58][59][60][61][62]. The aim of the present study is to use the existing crystallographic data to predict how structural changes upon activation change the resulting dynamics.…”

Section: Comparison To Experimental Studiesmentioning

confidence: 99%

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Surveying non-visual arrestins reveals allosteric interactions between functional sites

Seckler

Robinson

Lewis

et al. 2022

Preprint

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1.AbstractArrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modelling (ANM) together with our covariance compliment techniques to survey all of the available structures of the non-visual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain β-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.

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Section: Resultsmentioning

confidence: 99%

Section: X-ray Structure Selection and Analysismentioning

confidence: 99%

Section: Comparison To Experimental Studiesmentioning

confidence: 99%

Section: Comparison To Experimental Studiesmentioning

confidence: 99%

See 2 more Smart Citations

Surveying non-visual arrestins reveals allosteric interactions between functional sites

Seckler

Robinson

Lewis

et al. 2022

Preprint

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show abstract

“…These phosphorylation positions are conserved across species. By creating Asp-mutants that mimic one or more of these phosphosites, Kang et al studied their impact on arr conformation via hydrogen-deuterium exchange (HDX) experiments and crystallography [74]. Overall, they found that phosphomimetic mutation of S412 did not have a strong impact on barr-1 conformation and function.…”

Section: Identifying Functional Hot Spots Of Arrestin By Mutagenesismentioning

confidence: 99%

Biochemical insights into structure and function of arrestins

Aydin

Coin

2021

The FEBS Journal

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Arrestins (arr) are multifunctional cytosolic adaptors that bind to active and phosphorylated G protein-coupled receptors (GPCRs) via a highly versatile interface. Arrestins stop G protein signaling and trigger other signaling pathways. Recently, 3D structures of arr-GPCR complexes have been solved, which provide a bulk of structural information for understanding the mechanism of arr recruitment and activation. However, many questions about the functional consequences of structural details and the dynamics of the arr-GPCR interaction remain open. A wealth of information about key determinants for the arr-GPCR interaction and their functional relevance, and dynamic insights into the process of arr binding and the functional outcomes of different binding modes have been provided by a series of biochemical methods which we review here. Importantly, most of these methods provide information from the live cell, which is a necessary validation and complement for structural data. With the main focus on the most recent research, we will highlight major findings about arr structure, function, and dynamics derived from mutagenesis studies, cross-linking studies, conformational probes, and sensors, and we summarize available systems to detect arr recruitment. Furthermore, we discuss recent findings and directions of in silico investigations in arr-GPCR complexes.

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Surveying nonvisual arrestins reveals allosteric interactions between functional sites

et al. 2022

View full text Add to dashboard Cite

Arrestins are important scaffolding proteins that are expressed in all vertebrate animals. They regulate cell-signaling events upon binding to active G-protein coupled receptors (GPCR) and trigger endocytosis of active GPCRs. While many of the functional sites on arrestins have been characterized, the question of how these sites interact is unanswered. We used anisotropic network modeling (ANM) together with our covariance compliment techniques to survey all the available structures of the nonvisual arrestins to map how structural changes and protein-binding affect their structural dynamics. We found that activation and clathrin binding have a marked effect on arrestin dynamics, and that these dynamics changes are localized to a small number of distant functional sites. These sites include α-helix 1, the lariat loop, nuclear localization domain, and the C-domain β-sheets on the C-loop side. Our techniques suggest that clathrin binding and/or GPCR activation of arrestin perturb the dynamics of these sites independent of structural changes.

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Conformational Dynamics and Functional Implications of Phosphorylated β-Arrestins

Abstract: Highlights d The conformational effects of b-arrestin phosphorylation have been examined d S14D/T276D phospho-mimetic mutation of b-arrestin-2 induced conformational changes d S14D/T276D b-arrestin-2 shows features similar to the preactive state

Cited by 9 publications

References 43 publications

Surveying non-visual arrestins reveals allosteric interactions between functional sites

Surveying non-visual arrestins reveals allosteric interactions between functional sites

Biochemical insights into structure and function of arrestins

Surveying nonvisual arrestins reveals allosteric interactions between functional sites

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