Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members.
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| Title: | Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members. |
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| Authors: | Yussif, Baba M.1, Blasing, Cole V.1, Checco, James W.1,2 checco@unl.edu |
| Source: | Proceedings of the National Academy of Sciences of the United States of America. 3/14/2023, Vol. 120 Issue 11, p1-7. 27p. |
| Subjects: | Isomerization, G protein coupled receptors, Amino acid residues, Peptides, Post-translational modification |
| Abstract: | The l- to d-amino acid residue isomerization of neuropeptides is an understudied post-translational modification found in animals across several phyla. Despite its physiological importance, little information is available regarding the impact of endogenous peptide isomerization on receptor recognition and activation. As a result, the full roles peptide isomerization play in biology are not well understood. Here, we identify that the Aplysia allatotropin-related peptide (ATRP) signaling system utilizes l- to d-residue isomerization of one amino acid residue in the neuropeptide ligand to modulate selectivity between two distinct G protein-coupled receptors (GPCRs). We first identified a novel receptor for ATRP that is selective for the D2-ATRP form, which bears a single d-phenylalanine residue at position 2. Using cell-based receptor activation experiments, we then characterized the stereoselectivity of the two known ATRP receptors for both endogenous ATRP diastereomers, as well as for homologous toxin peptides from a carnivorous predator. We found that the ATRP system displayed dual signaling through both the Gαq and Gαs pathways, and each receptor was selectively activated by one naturally occurring ligand diastereomer over the other. Overall, our results provide insights into an unexplored mechanism by which nature regulates intercellular communication. Given the challenges in detecting l- to d-residue isomerization from complex mixtures de novo and in identifying receptors for novel neuropeptides, it is likely that other neuropeptide-receptor systems may also utilize changes in stereochemistry to modulate receptor selectivity in a manner similar to that discovered here. [ABSTRACT FROM AUTHOR] |
| Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.) | |
| Database: | Engineering Source |
| FullText | Text: Availability: 0 |
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| Header | DbId: egs DbLabel: Engineering Source An: 162315276 AccessLevel: 6 PubType: Academic Journal PubTypeId: academicJournal PreciseRelevancyScore: 0 |
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| Items | – Name: Title Label: Title Group: Ti Data: Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members. – Name: Author Label: Authors Group: Au Data: <searchLink fieldCode="AR" term="%22Yussif%2C+Baba+M%2E%22">Yussif, Baba M.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Blasing%2C+Cole+V%2E%22">Blasing, Cole V.</searchLink><relatesTo>1</relatesTo><br /><searchLink fieldCode="AR" term="%22Checco%2C+James+W%2E%22">Checco, James W.</searchLink><relatesTo>1,2</relatesTo><i> checco@unl.edu</i> – Name: TitleSource Label: Source Group: Src Data: <searchLink fieldCode="JN" term="%22Proceedings+of+the+National+Academy+of+Sciences+of+the+United+States+of+America%22">Proceedings of the National Academy of Sciences of the United States of America</searchLink>. 3/14/2023, Vol. 120 Issue 11, p1-7. 27p. – Name: Subject Label: Subjects Group: Su Data: <searchLink fieldCode="DE" term="%22Isomerization%22">Isomerization</searchLink><br /><searchLink fieldCode="DE" term="%22G+protein+coupled+receptors%22">G protein coupled receptors</searchLink><br /><searchLink fieldCode="DE" term="%22Amino+acid+residues%22">Amino acid residues</searchLink><br /><searchLink fieldCode="DE" term="%22Peptides%22">Peptides</searchLink><br /><searchLink fieldCode="DE" term="%22Post-translational+modification%22">Post-translational modification</searchLink> – Name: Abstract Label: Abstract Group: Ab Data: The l- to d-amino acid residue isomerization of neuropeptides is an understudied post-translational modification found in animals across several phyla. Despite its physiological importance, little information is available regarding the impact of endogenous peptide isomerization on receptor recognition and activation. As a result, the full roles peptide isomerization play in biology are not well understood. Here, we identify that the Aplysia allatotropin-related peptide (ATRP) signaling system utilizes l- to d-residue isomerization of one amino acid residue in the neuropeptide ligand to modulate selectivity between two distinct G protein-coupled receptors (GPCRs). We first identified a novel receptor for ATRP that is selective for the D2-ATRP form, which bears a single d-phenylalanine residue at position 2. Using cell-based receptor activation experiments, we then characterized the stereoselectivity of the two known ATRP receptors for both endogenous ATRP diastereomers, as well as for homologous toxin peptides from a carnivorous predator. We found that the ATRP system displayed dual signaling through both the Gαq and Gαs pathways, and each receptor was selectively activated by one naturally occurring ligand diastereomer over the other. Overall, our results provide insights into an unexplored mechanism by which nature regulates intercellular communication. Given the challenges in detecting l- to d-residue isomerization from complex mixtures de novo and in identifying receptors for novel neuropeptides, it is likely that other neuropeptide-receptor systems may also utilize changes in stereochemistry to modulate receptor selectivity in a manner similar to that discovered here. [ABSTRACT FROM AUTHOR] – Name: AbstractSuppliedCopyright Label: Group: Ab Data: <i>Copyright of Proceedings of the National Academy of Sciences of the United States of America is the property of National Academy of Sciences and its content may not be copied or emailed to multiple sites without the copyright holder's express written permission. Additionally, content may not be used with any artificial intelligence tools or machine learning technologies. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract.</i> (Copyright applies to all Abstracts.) |
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| RecordInfo | BibRecord: BibEntity: Identifiers: – Type: doi Value: 10.1073/pnas.2217604120 Languages: – Code: eng Text: English PhysicalDescription: Pagination: PageCount: 27 StartPage: 1 Subjects: – SubjectFull: Isomerization Type: general – SubjectFull: G protein coupled receptors Type: general – SubjectFull: Amino acid residues Type: general – SubjectFull: Peptides Type: general – SubjectFull: Post-translational modification Type: general Titles: – TitleFull: Endogenous l- to d-amino acid residue isomerization modulates selectivity between distinct neuropeptide receptor family members. Type: main BibRelationships: HasContributorRelationships: – PersonEntity: Name: NameFull: Yussif, Baba M. – PersonEntity: Name: NameFull: Blasing, Cole V. – PersonEntity: Name: NameFull: Checco, James W. IsPartOfRelationships: – BibEntity: Dates: – D: 14 M: 03 Text: 3/14/2023 Type: published Y: 2023 Identifiers: – Type: issn-print Value: 00278424 Numbering: – Type: volume Value: 120 – Type: issue Value: 11 Titles: – TitleFull: Proceedings of the National Academy of Sciences of the United States of America Type: main |
| ResultId | 1 |
