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Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation

Nature Structural & Molecular Biology volume 25, pages 538–545 (2018)Cite this article

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Abstract

Arrestins regulate the signaling of ligand-activated, phosphorylated G-protein-coupled receptors (GPCRs). Different patterns of receptor phosphorylation (phosphorylation barcode) can modulate arrestin conformations, resulting in distinct functional outcomes (for example, desensitization, internalization, and downstream signaling). However, the mechanism of arrestin activation and how distinct receptor phosphorylation patterns could induce different conformational changes on arrestin are not fully understood. We analyzed how each arrestin amino acid contributes to its different conformational states. We identified a conserved structural motif that restricts the mobility of the arrestin finger loop in the inactive state and appears to be regulated by receptor phosphorylation. Distal and proximal receptor phosphorylation sites appear to selectively engage with distinct arrestin structural motifs (that is, micro-locks) to induce different arrestin conformations. These observations suggest a model in which different phosphorylation patterns of the GPCR C terminus can combinatorially modulate the conformation of the finger loop and other phosphorylation-sensitive structural elements to drive distinct arrestin conformation and functional outcomes.

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Fig. 1: The arrestin signaling cycle.
Fig. 2: Systematic comparison of arrestin structures.
Fig. 3: An ionic lock keeps the finger loop in the inactive state.
Fig. 4: Analysis of arrestin residues that interact with receptor-attached phosphates.
Fig. 5: Summary of phosphorylation-sensitive motifs for arrestin activation.

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Acknowledgements

We thank J. Standfuss for discussing the results of previous mutagenesis experiments and X. Deupi, D. Veprintsev, D. Meyer, G. F. X. Schertler, S. Chavali, P. Lakshminarasimhan, and H. Harbrecht for their comments on the manuscript. This work was supported by the Medical Research Council (MC_U105185859; M.M.B., T.F., and A. Sente) and the Boehringer Ingelheim Fond (T.F.). A. Sente was funded by a Wolfson College Research Grant, MRC Summer Studentship, and The Lister Institute Summer Studentship. M.M.B. is a Lister Institute Research Prize Fellow and is supported by an ERC Consolidator Grant. The research program in the laboratory of A.K.S. is supported by an Intermediate Fellowship from the Wellcome Trust DBT India Alliance (IA/I/14/1/501285). T.F. is a Research Fellow of Fitzwilliam College, University of Cambridge, UK.

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Authors and Affiliations

  1. MRC Laboratory of Molecular Biology, Cambridge, UK

    Andrija Sente, Raphael Peer, Arthur M. Lesk, Santhanam Balaji, M. Madan Babu & Tilman Flock

  2. Department of Biological Sciences and Bioengineering, Indian Institute of Technology, Kanpur, India

    Ashish Srivastava, Mithu Baidya & Arun K. Shukla

  3. Department of Biochemistry and Molecular Biology and Huck Institutes of Life Sciences, Pennsylvania State University, University Park, PA, USA

    Arthur M. Lesk

  4. Fitzwilliam College, University of Cambridge, Cambridge, UK

    Tilman Flock

  5. Laboratory of Biomolecular Research, Division of Biology and Chemistry, Paul Scherrer Institute, Villigen, Switzerland

    Tilman Flock

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Contributions

A. Sente and T.F. collected data. A. Sente, R.P., and T.F. wrote scripts and processed the data. S.B. generated the arrestin alignment. A.M.L. helped with analyzing conformational changes. A. Srivastava, M.B., and A.K.S. designed and performed bimane fluorescence experiments. All of the authors analyzed and interpreted the results. A. Sente, M.M.B., and T.F. wrote the manuscript with input from all of the authors. M.M.B. and T.F. designed and supervised the project.

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Correspondence to Andrija Sente, M. Madan Babu or Tilman Flock.

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Integrated supplementary information

Supplementary Figure 1 Clustering arrestin structures by their residue contact fingerprints to assign structures to signaling states.

Clustering arrestin structures by residue contact fingerprints separates active and inactive arrestins. Within the cluster of inactive arrestins, visual and β-arrestins cluster separately. Furthermore, rod and cone arrestins cluster separately within the branch of visual arrestins. 3GD1 and 3GC3 are co-crystallized with a clathrin, but similar to the inactive structure. Moreover, structures 3UGU and 3UGX, which are thought to be structures of pre-activated arrestins, cluster with other inactive state structures and were considered to be inactive in further analysis.

Supplementary Figure 2 Analysis of arrestin subtypes with focus on β-arrestins.

a, Clustering arrestin structures by residue contact fingerprints separates active and inactive arrestins. Within the cluster of inactive state structures, the method clearly distinguishes between visual and β-arrestins, and within the subcluster of visual arrestins separates rod and cone arrestins. Extracting the features (contacts) that determine the clustering pattern enables the analysis of differences between visual and β-arrestins. b, Contacts that are only present in β-arrestins and absent from visual arrestins (see the Methods for details). c, Contacts shown in b plotted on the structure (PDB 1G4R, chain A). Most of the contacts unique to β-arrestins seem to occur in the C domain. For instance, there seems to be a group of contacts stabilizing the distal part of the body of the C domain. d, Sequence analysis showing that the most variable region (sequence-wise) between visual and β-arrestins is the region surrounding the C-loop (C.s15s16). Given that this loop is known to interact with transmembrane helix 4 of the receptor, it is possible that the sequence differences identified here might be important in determining the differences in receptor selectivity across different arrestin subtypes.

Supplementary Figure 3 Analysis of arrestin subtypes with focus on visual arrestins.

a, Contacts that are only present in visual arrestins and absent from β-arrestins. b, Contacts shown in a plotted onto the structure (PDB 1CF1, chain D). The analysis reveals a number of inter-domain contacts present uniquely in visual arrestins. Moreover, the region around the C-loop seems to be stabilized by additional contacts absent from β-arrestins. The region around the C-loop (C.s15s16) is the most variable region in terms of the amino acid sequence between visual and β-arrestins (Supplementary Fig. 3d) and hence could account for functional differences in visual and β-arrestins.

Supplementary Figure 4 Extended analysis of the finger loop conformation in all inactive state arrestin structures.

a, Comparison of the finger loop lock in all crystal structures of inactive arrestin showing that in all cases where the lock is not perfectly engaged, crystal contacts with other monomers in the asymmetric unit are present. b,c, Example of interchain contacts that affect the conformation of the finger loop (PDB 1CF1, chains B and C).

Supplementary Figure 5 Bimane fluorescence assay confirms the existence of multiple finger loop conformations.

a–c, Conformational rearrangement in the finger loop of β-arrestins upon their interaction with the tail phosphopeptide (V2Rpp) and full receptor (β2V2R). Monobromobimane (mBBr) is chemically attached to a cysteine engineered in the finger loop of β-arrestins at positions L68N.s5s6.5 (β-arrestin-1) and L69N.s5s6.5 (β-arrestin-2). A change in fluorescence reflects conformational change or a change in environment (and thereby fluorescence quenching) of the finger loop. a,b, Purified βarr1mBBr (a) and βarr2mBBr (b) were incubated with either V2Rpp or β2V2R (agonist bound and phosphorylated) (molar ratio of βarr1:V2Rpp/ β2V2R 1:3 in a concentration range of 1–5 μM). The fluorescence intensity of βarrmBBr alone was measured and used as the normalization reference (maximum value treated as 100%). Bimane fluorescence at λmax is presented as a bar graph (right). Values represent the mean ± s.e.m. of 4–5 independent experiments analyzed using one-way ANOVA with Bonferroni post-test (**P < 0.01; ***P < 0.001). The fluorescence intensity of βarrmBBr increases upon its interaction with V2Rpp, while it decreases upon interaction with β2V2R. We note that the patterns of bimane fluorescence observed here differ from those reported in the literature for the rhodopsin–arrestin-1 system (J. Biol. Chem. 280, 6861–6871, 2005; J. Biol. Chem. 281, 9407–9417, 2006). These differences likely arise from significantly different experimental conditions (e.g., protein concentrations, buffer conditions, optical setting, receptor environment, etc.). c, Schematic representation of tail-engaged and fully engaged receptor– β-arrestin complexes depicting the changes in finger loop conformation and environment.

Supplementary Figure 6 Effects of alanine mutations of finger loop lock residues on arrestin binding to the receptor.

Mutating the two arginines appears to increase binding of arrestin to the receptor, presumably by pre-releasing the finger loop in an ‘open’ conformation. Such an effect is not observed when finger loop residues are mutated, possibly because it interferes with binding to the receptor. The absence of increased receptor binding for N.S6.2 in the dataset of Peterhans et al. may potentially arise from different experimental conditions (Methods). Number (n) within each bar indicates the number of independent experiments for the given mutant arrestin.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–6

Reporting Summary

Supplementary Table 1

The table shows (tab 1) an overview of structures that contain an arrestin domain and (tab 2) information about the structure parameters and associated publications

Supplementary Table 2

The table contains information about the conformation of the finger loop in inactive state arrestin structures

Supplementary Table 3

The table contains mapping of Common Arrestin Numbering (CAN) to published arrestin structures

Supplementary Dataset 1

Common Arrestin Numbering (CAN). The top plot shows the ‘consensus secondary structure’ of arrestin. The alignment shows structurally equivalent positions for all known arrestin structures. The bottom plot highlights frequencies to find a secondary structure at equivalent positions in different arrestin structures

Supplementary Dataset 2

Arrestin subtype analysis alignment. Sequence alignment of arrestin orthologs (fasta format)

Supplementary Dataset 3

Arrestin Residue Contact Networks (RCNs). Dataset containing intra-arrestin residue contacts of 18 structures analyzed in the paper (Methods)

Source Data, Supplementary Figure 5

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Sente, A., Peer, R., Srivastava, A. et al. Molecular mechanism of modulating arrestin conformation by GPCR phosphorylation. Nat Struct Mol Biol 25, 538–545 (2018). https://doi.org/10.1038/s41594-018-0071-3

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