AI protein structure prediction-based modeling and mutagenesis of a protostome receptor and peptide ligands reveal key residues for their interaction

Guo, Shi-Qi; Li, Yadong; Chen, Ping; Zhang, Guo; Wang, Huiying; Jiang, Hui-Min; Liu, Weijia; Xu, Ju-Ping; Ding, Xueying; Fu, Ping; Yu, Ke; Zhou, Haibo; Checco, James W.; Jing, Jian

doi:10.1016/j.jbc.2022.102440

Cited by 7 publications

(7 citation statements)

References 103 publications

(203 reference statements)

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“…In summary, our study provides a relatively complete description of the Aplysia vasopressin signaling system by identifying the precursor and two receptors and exploring the roles of PTMs and individual residues in receptor activity. Future work could investigate how the peptide ligand might interact with the receptors and possibly explain how PTMs and individual residues might contribute to receptor activation through structural modeling ( Guo et al, 2022 ). Additionally, the physiological actions of the Aplysia vasotocin signaling system need to be explored more extensively.…”

Section: Discussionmentioning

confidence: 99%

“…We formally tested the roles of individual residues on receptor activity by performing alanine substitution experiments. Many previous studies have shown that Frontiers in Pharmacology frontiersin.org changes in evolutionarily conserved residues in peptide ligands have a significant impact on, and usually are necessary for, receptor activity (Guo et al, 2022). For oxytocin/vasopressin, except for cysteine residues, the residues at the position of 5, 7, and 9 are more evolutionarily conserved than the other residues.…”

Section: Actions Of Ptms and Single Residues Of Apvt On Receptor Acti...mentioning

confidence: 99%

“…We sought to study an oxytocin/vasopressin signaling system in the gastropod mollusc Aplysia californica . Aplysia is an experimentally-advantageous system and has provided fundamental insight into the neural basis of motivated behaviors ( Jing and Weiss, 2002 ; Jing et al, 2004 ; Sasaki et al, 2009 ; Jing et al, 2010 ; Sasaki et al, 2013 ; Zhang et al, 2020 ; Bedecarrats et al, 2021 ; Evans et al, 2021 ; Due et al, 2022 ; Wang et al, 2023 ), learning and memory ( Sieling et al, 2014 ; Byrne and Hawkins, 2015 ; Orvis et al, 2022 ) and neuromodulation ( Cropper et al, 2018b ; Zhang et al, 2022 ), including neuropeptides ( Livnat et al, 2016 ; Zhang et al, 2017 ; Do et al, 2018 ; Zhang et al, 2018 ; Chan-Andersen et al, 2022 ) and receptors ( Bauknecht and Jekely, 2015 ; Checco et al, 2018 ; Guo et al, 2022 ; Jiang et al, 2022 ; Zhang et al, 2022 ). The first evidence for the presence of oxytocin/vasopressin-related neuropeptide in protostomes comes from an early immunohistochemical study ( Remy et al, 1979 ), and the later identification of an arginine vasopressin-like diuretic hormone ( Proux et al, 1987 ), both in insects.…”

Section: Introductionmentioning

confidence: 99%

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Characterization of an Aplysia vasotocin signaling system and actions of posttranslational modifications and individual residues of the ligand on receptor activity

Ding

Guo

et al. 2023

Front. Pharmacol.

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The vasopressin/oxytocin signaling system is present in both protostomes and deuterostomes and plays various physiological roles. Although there were reports for both vasopressin-like peptides and receptors in mollusc Lymnaea and Octopus, no precursor or receptors have been described in mollusc Aplysia. Here, through bioinformatics, molecular and cellular biology, we identified both the precursor and two receptors for Aplysia vasopressin-like peptide, which we named Aplysia vasotocin (apVT). The precursor provides evidence for the exact sequence of apVT, which is identical to conopressin G from cone snail venom, and contains 9 amino acids, with two cysteines at position 1 and 6, similar to nearly all vasopressin-like peptides. Through inositol monophosphate (IP1) accumulation assay, we demonstrated that two of the three putative receptors we cloned from Aplysia cDNA are true receptors for apVT. We named the two receptors as apVTR1 and apVTR2. We then determined the roles of post-translational modifications (PTMs) of apVT, i.e., the disulfide bond between two cysteines and the C-terminal amidation on receptor activity. Both the disulfide bond and amidation were critical for the activation of the two receptors. Cross-activity with conopressin S, annetocin from an annelid, and vertebrate oxytocin showed that although all three ligands can activate both receptors, the potency of these peptides differed depending on their residue variations from apVT. We, therefore, tested the roles of each residue through alanine substitution and found that each substitution could reduce the potency of the peptide analog, and substitution of the residues within the disulfide bond tended to have a larger impact on receptor activity than the substitution of those outside the bond. Moreover, the two receptors had different sensitivities to the PTMs and single residue substitutions. Thus, we have characterized the Aplysia vasotocin signaling system and showed how the PTMs and individual residues in the ligand contributed to receptor activity.

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Section: Discussionmentioning

confidence: 99%

Section: Actions Of Ptms and Single Residues Of Apvt On Receptor Acti...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Characterization of an Aplysia vasotocin signaling system and actions of posttranslational modifications and individual residues of the ligand on receptor activity

Ding

Guo

et al. 2023

Front. Pharmacol.

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“…The results further supported that the APGWa and MIP signaling systems are somewhat related. In the future, it would be of interest to determine why MIP1, 4, 7, and 8 ligands could activate APGWa-R1 but not activate APGWa-R2 and APGWa-R3, perhaps based on the receptor structure and difference in specific residues in the receptors by using AI-based protein structure prediction and mutagenesis of the receptors …”

Section: Discussionmentioning

confidence: 99%

“…In the current work, we sought to characterize two Wamide neuropeptide signaling systems: GWa and MIP families, in a model system, mollusk Aplysia californica . Aplysia has emerged in recent years as a powerful lophotrochozoan/spiralians laboratory animal for the study of neuronal circuits, − motivated behaviors, ,− and neuromodulation. ,− …”

Section: Introductionmentioning

confidence: 99%

Molecular Characterization of Two Wamide Neuropeptide Signaling Systems in Mollusk Aplysia

Wang

Liu

et al. 2023

ACS Chem. Neurosci.

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Neuropeptides with the C-terminal Wamide (Trp-NH 2 ) are one of the last common ancestors of peptide families of eumetazoans and play various physiological roles. In this study, we sought to characterize the ancient Wamide peptides signaling systems in the marine mollusk Aplysia californica, i.e., APGWamide (APGWa) and myoinhibitory peptide (MIP)/Allatostatin B (AST-B) signaling systems. A common feature of protostome APGWa and MIP/AST-B peptides is the presence of a conserved Wamide motif in the C-terminus. Although orthologs of the APGWa and MIP signaling systems have been studied to various extents in annelids or other protostomes, no complete signaling systems have yet been characterized in mollusks. Here, through bioinformatics, molecular and cellular biology, we identified three receptors for APGWa, namely, APGWa-R1, APGWa-R2, and APGWa-R3. The EC 50 values for APGWa-R1, APGWa-R2, and APGWa-R3 are 45, 2100, and 2600 nM, respectively. For the MIP signaling system, we predicted 13 forms of peptides, i.e., MIP1−13 that could be generated from the precursor identified in our study, with MIP5 (WKQMAVWa) having the largest number of copies (4 copies). Then, a complete MIP receptor (MIPR) was identified and the MIP1−13 peptides activated the MIPR in a dose-dependent manner, with EC 50 values ranging from 40 to 3000 nM. Peptide analogs with alanine substitution experiments demonstrated that the Wamide motif at the C-terminus is necessary for receptor activity in both the APGWa and MIP systems. Moreover, cross-activity between the two signaling systems showed that MIP1, 4, 7, and 8 ligands could activate APGWa-R1 with a low potency (EC 50 values: 2800−22,000 nM), which further supported that the APGWa and MIP signaling systems are somewhat related. In summary, our successful characterization of Aplysia APGWa and MIP signaling systems represents the first example in mollusks and provides an important basis for further functional studies in this and other protostome species. Moreover, this study may be useful for elucidating and clarifying the evolutionary relationship between the two Wamide signaling systems (i.e., APGWa and MIP systems) and their other extended neuropeptide signaling systems.

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Synergistic integration of deep learning with protein docking in cardiovascular disease treatment strategies

Yakoubi

2024

IUBMB Life

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This research delves into the exploration of the potential of tocopherol‐based nanoemulsion as a therapeutic agent for cardiovascular diseases (CVD) through an in‐depth molecular docking analysis. The study focuses on elucidating the molecular interactions between tocopherol and seven key proteins (1O8a, 4YAY, 4DLI, 1HW9, 2YCW, 1BO9 and 1CX2) that play pivotal roles in CVD development. Through rigorous in silico docking investigations, assessment was conducted on the binding affinities, inhibitory potentials and interaction patterns of tocopherol with these target proteins. The findings revealed significant interactions, particularly with 4YAY, displaying a robust binding energy of −6.39 kcal/mol and a promising Ki value of 20.84 μM. Notable interactions were also observed with 1HW9, 4DLI, 2YCW and 1CX2, further indicating tocopherol's potential therapeutic relevance. In contrast, no interaction was observed with 1BO9. Furthermore, an examination of the common residues of 4YAY bound to tocopherol was carried out, highlighting key intermolecular hydrophobic bonds that contribute to the interaction's stability. Tocopherol complies with pharmacokinetics (Lipinski's and Veber's) rules for oral bioavailability and proves safety non‐toxic and non‐carcinogenic. Thus, deep learning‐based protein language models ESM1‐b and ProtT5 were leveraged for input encodings to predict interaction sites between the 4YAY protein and tocopherol. Hence, highly accurate predictions of these critical protein–ligand interactions were achieved. This study not only advances the understanding of these interactions but also highlights deep learning's immense potential in molecular biology and drug discovery. It underscores tocopherol's promise as a cardiovascular disease management candidate, shedding light on its molecular interactions and compatibility with biomolecule‐like characteristics.

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AI protein structure prediction-based modeling and mutagenesis of a protostome receptor and peptide ligands reveal key residues for their interaction

Cited by 7 publications

References 103 publications

Characterization of an Aplysia vasotocin signaling system and actions of posttranslational modifications and individual residues of the ligand on receptor activity

Characterization of an Aplysia vasotocin signaling system and actions of posttranslational modifications and individual residues of the ligand on receptor activity

Molecular Characterization of Two Wamide Neuropeptide Signaling Systems in Mollusk Aplysia

Synergistic integration of deep learning with protein docking in cardiovascular disease treatment strategies

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