Structure-activity relationship studies on the endogenous neuroactive tetrapeptide achatin-I on giant neurons of Ferussac

Kim, Kah H.; Takeuchi, Hiroshi; Kamatani, Yoshimi; Minakata, Hiroyuki; Nomoto, Kyosuke

doi:10.1016/0024-3205(91)90131-t

Cited by 18 publications

(6 citation statements)

References 3 publications

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“…The structure of GdFAD (also known as achatin I), a homologue of GdFFD, has been solved using X-ray crystallography by Kim et al 57 The X-ray structure shows a bent conformation resembling a cyclic conformation, similar to the structure predicted by our modeling approach. While the sidechain positions of [ d -Phe] 2 and [ l -Asp] 4 are slightly different, both agree on the proximity between the amino group at the N-terminus and the β-carboxyl group at the C-terminus.…”

Section: Resultssupporting

confidence: 63%

Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit

Thanh

Checco

Tro

et al. 2018

Phys. Chem. Chem. Phys.

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Proteins and peptides in nature are almost exclusively made from l-amino acids, and this is even more absolute in the metazoan. With the advent of modern bioanalytical techniques, however, previously unappreciated roles for d-amino acids in biological processes have been revealed. Over 30 d-amino acid containing peptides (DAACPs) have been discovered in animals where at least one l-residue has been isomerized to the d-form via an enzyme-catalyzed process. In Aplysia californica, GdFFD and GdYFD (the lower-case letter "d" indicates a d-amino acid residue) modulate the feeding behavior by activating the Aplysia achatin-like neuropeptide receptor (apALNR). However, little is known about how the three-dimensional conformation of DAACPs influences activity at the receptor, and the role that d-residues play in these peptide conformations. Here, we use a combination of computational modeling, drift-tube ion-mobility mass spectrometry, and receptor activation assays to create a simple model that predicts bioactivities for a series of GdFFD analogs. Our results suggest that the active conformations of GdFFD and GdYFD are similar to their lowest energy conformations in solution. Our model helps connect the predicted structures of GdFFD analogs to their activities, and highlights a steric effect on peptide activity at position 1 on the GdFFD receptor apALNR. Overall, these methods allow us to understand ligand-receptor interactions in the absence of high-resolution structural data.

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Section: Resultssupporting

confidence: 63%

Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit

Thanh

Checco

Tro

et al. 2018

Phys. Chem. Chem. Phys.

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“…Prior to our work, Bauknecht et al showed d -Phe-specific activation of apALNR by GdFFD-OH, but little else about this ligand–receptor family has been studied. Although previous studies , have explored how DAACP structure relates to specific physiological functions (e.g., neuronal activity or muscle contraction), the receptors for most cell–cell signaling DAACPs have not been identified, and thus, little is known about the interactions of DAACPs with their receptors throughout the CNS. Here, we provide multiple compelling lines of evidence demonstrating that apALNR does indeed function as a receptor for the apALNP-derived DAACPs GdFFD-OH and GdYFD-OH and mediates multiple physiological effects throughout the CNS.…”

Section: Resultsmentioning

confidence: 99%

Molecular and Physiological Characterization of a Receptor for d-Amino Acid-Containing Neuropeptides

et al. 2018

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Neuropeptides in several animals undergo an unusual post-translational modification, the isomerization of an amino acid residue from the l-stereoisomer to the d-stereoisomer. The resulting d-amino acid-containing peptide (DAACP) often displays biological activity higher than that of its all-l-residue analogue, with the d-residue being critical for function in many cases. However, little is known about the full physiological roles played by DAACPs, and few studies have examined the interaction of DAACPs with their cognate receptors. Here, we characterized the signaling of several DAACPs derived from a single neuropeptide prohormone, the Aplysia californica achatin-like neuropeptide precursor (apALNP), at their putative receptor, the achatin-like neuropeptide receptor (apALNR). We first used quantitative polymerase chain reaction and in situ hybridization experiments to demonstrate receptor (apALNR) expression throughout the central nervous system; on the basis of the expression pattern, we identified novel physiological functions that may be mediated by apALNR. To gain insight into ligand signaling through apALNR, we created a library of native and non-native neuropeptide analogues derived from apALNP (the neuropeptide prohormone) and evaluated them for activity in cells co-transfected with apALNR and the promiscuous Gα subunit Gα-16. Several of these neuropeptide analogues were also evaluated for their ability to induce circuit activity in a well-defined neural network associated with feeding behavior in intact ganglia from Aplysia. Our results reveal the specificity of apALNR and provide strong evidence that this receptor mediates diverse physiological functions throughout the central nervous system. Finally, we show that some native apALNP-derived DAACPs exhibit enhanced stability toward endogenous proteases, suggesting that the d-residues in these DAACPs may increase the peptide lifetime, in addition to influencing receptor specificity, in the nervous system. Ultimately, these studies provide insight into signaling at one of the few known DAACP-specific receptors and advance our understanding of the roles that l- to d-residue isomerization play in neuropeptide signaling.

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“…Achatin-I induces a voltage-dependent inward current due to sodium ions on the identifiable neurons [ 1,2], and is likely to play an important role as an excitatory neurotransmitter in the heart regulation of A. fulica [3]. The neuroactivity of achatin-I is stereospecific, and no other stereoisomers which are replaced with L-or D-amino acid residues show such a biological effect [1,2].…”

Section: Introductionmentioning

confidence: 99%

“…The neuroactivity of achatin-I is stereospecific, and no other stereoisomers which are replaced with L-or D-amino acid residues show such a biological effect [1,2]. This means that a strict stereospecificity is required for the interaction with the receptor on Achatina neurons.…”

Section: Introductionmentioning

confidence: 99%

Molecular conformation of achatin‐I, an endogenous neuropeptide containing D‐amino acid residue

et al. 1990

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The molecular conformation of achatin‐I neutral form (H‐Gly‐D‐Phe‐Ala‐Asp‐OH), an endogenous neuropeptide, was elucidated by X‐ray crystal analysis. The molecule has a type II' β‐turn structure with the D‐Phe‐Ala residues at the corner of the bend, which is further stabilized by two NH(Gly)βCγ=Oδ(Asp) and NH(Asp)βCγ=Oδ(Asp) intramolecular hydrogen bonds. This turn conformation may be an important feature of achatin‐I related to its neuroexcitatory activity.

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Structure-activity relationship studies on the endogenous neuroactive tetrapeptide achatin-I on giant neurons of Ferussac

Cited by 18 publications

References 3 publications

Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit

Conformational investigation of the structure–activity relationship of GdFFD and its analogues on an achatin-like neuropeptide receptor of Aplysia californica involved in the feeding circuit

Molecular and Physiological Characterization of a Receptor for d-Amino Acid-Containing Neuropeptides

Molecular conformation of achatin‐I, an endogenous neuropeptide containing D‐amino acid residue

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