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. 2022 Aug 18;3(5):zqac038.
doi: 10.1093/function/zqac038. eCollection 2022.

Hitting the Detection Limit in cAMP Signaling

Florencia Klein  1 , Matías R Machado  1 , Sergio Pantano  1
Affiliations

Hitting the Detection Limit in cAMP Signaling

Florencia Klein et al. Function (Oxf). .
No abstract available

Keywords: CUTie sensor; compartmentalization; concentration; cyclic nucleotide; myofibril; nanodomain; sarcomere; subcellular localization.

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Conflict of interest statement

Authors declare no conflict of interest.

Figures

Figure 1:
Figure 1:
In-scale molecular representation of cAMP nanosignalosomes. (A) Nanosignalosome around the Glucagon-like peptide 1 (GLP-1) receptor. The structural model is based on reference 6, and all components are represented in scale relative to the 30 nm hemisphere. The model includes a membrane patch embedding the structures of the GLP-1 receptor (orange, PDBid: 6X18) and adenylyl cyclase (AC, brown, generated by AlphaFold2, https://alphafold.ebi.ac.uk/entry/P40145). The linker between the GLP-1 receptor and a model of the EPAC1-camps sensor is schematically represented as a ruler, and the semitransparent surface indicates a 30 nm radius semispherical volume. A holotetramer of PKA (PDBid: 3J4Q) with the R- and C-subunits colored pink and magenta is arbitrarily located within the nanosignalosome. The binding site of a yet undetermined AKAP is schematically indicated attached to the DD domain. The catalytic domains of 3 PDEs (PDBid:1SOJ) are arbitrarily placed near the borders of the nanodomain, just as a reference for the relative dimensions. To illustrate the size differences, ATP and cAMP molecules are placed nearby the AC and CNBDs (colored in violet and red, respectively). All molecules are represented by their solvent-accessible surface. Note that ATP and cAMP molecules occupy a comparably small but distinguishable portion of space within the nanosignalosome. (B) Structural model of a myofibril segment. Progressive close-ups of the myofibril are shown from left to right. The thick filament, including myosin, titin, and MyBP-C proteins, is shown in blue (based on PDB structures 3DTP and 3LPW). The volume discussed in the main text was calculated as that of a hollow cylinder, excluding the central region occupied by the thick filament. Excluding the space associated with the thin filament proteins reduces the nanosignalosome compartment to nearly half of its original value. The thin filaments are composed of actin filaments (gray) and tropomyosin (light blue), taken from the PDB structure 2W4U. Troponin systems taken from the PDB id 1J1D are structurally aligned on the previously mentioned structure of the thin filament (TnT, TnI, and TnC, red, orange, and brown, respectively). The thin filaments are aligned in a hexameric configuration centered on the thick filament, according to cryogenic electron microscopy (CryoEM) data. This structure is then replicated in space. The semitransparent cylindrical surface indicates the proposed nanosignalosome that repeats itself in space. A 30 nm ruler is added to facilitate the comparison with panel A. (C) Cartoon representations of skeletal and cardiac muscle troponin systems colored as in B. The protein segment proposed as AKAP in the cardiac TnT is shown with all-atoms representation, and the helix-breaking proline residue in the skeletal TnT is highlighted. (D) Multiple sequence alignment of the region reported as AKAP in TnT. The helix-breaking proline is highlighted in red. Structural models were built using in-house scripts and PACKMOL (http://leandro.iqm.unicamp.br/m3g/packmol/home.shtml). Protein sequences were retrieved from the Uniprot database (http://uniprot.org). Graphics were rendered using VMD (https://www.ks.uiuc.edu/Research/vmd/).
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References

    1. Zaccolo M, Zerio A, Lobo MJ.. Subcellular organization of the cAMP signaling pathway. Pharmacol Rev. 2021;73:(1):278–309. - PMC - PubMed
    1. Omar MH, Scott JD.. AKAP signaling islands: venues for precision pharmacology. Trends Pharmacol Sci. 2020;41:(12):933–946. - PMC - PubMed
    1. Smith FD, Reichow SL, Esseltine JLet al. . Intrinsic disorder within an AKAP-protein kinase A complex guides local substrate phosphorylation. Elife. 2013;2:e01319. DOI:10.7554/eLife.01319 - DOI - PMC - PubMed
    1. Anton SE, Kayser C, Maiellaro Iet al. . Receptor-associated independent cAMP nanodomains mediate spatiotemporal specificity of GPCR signaling. Cell. 2022;185:(7):1130–1142. - PubMed
    1. Surdo NC, Berrera M, Koschinski Aet al. . FRET biosensor uncovers cAMP nano-domains at b-adrenergic targets that dictate precise tuning of cardiac contractility. Nat Commun. 2017;8:(1):1–14.. DOI:10.1038/ncomms15031 - DOI - PMC - PubMed

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