Arginine to citrulline replacement in substrates of phosphorylase kinase

Bartleson, Cheryl; Luo, Siquan; Graves, Donald J.; Martin, Bruce L.

doi:10.1016/s0167-4838(00)00100-x

Cited by 3 publications

(4 citation statements)

References 11 publications

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“…Figure 2). 19 Whereas replacement of Arg 1 by citrulline (14) did not affect the Y 4 R affinity, incorporation of citrulline instead of Arg 3 (15) and Arg 5 (16) resulted in a decrease in Y 4 R affinity by more than a factor of 10 (see Table 1). This suggested a minor relevance of the basic side chain of Arg 1 for Y 4 R binding.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

“…Purification by preparative HPLC (system 1, gradient: 0− 18 min MeCN/0.1% aq TFA 3:97 to 42:58, t R = 13 min) yielded 18 as a white solid (13.5 mg, 40%). 1 A c e t y l -A r g -G l y -A r g -L e u -A r g -T y r -A m i d e T r i s -(hydrotrifluoroacetate) (19). Peptide 19 was synthesized on a Sieber-amide-PS resin (40 mg, 0.65 mmol/g) according to the general N α -S u c c i n y l -A r g -T y r -A r g -L e u -A r g -T y r -A m i d e T r i s -(hydrotrifluoroacetate) (20).…”

Section: ■ Experimental Sectionmentioning

confidence: 99%

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Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

et al. 2020

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Within the family of neuropeptide Y (NPY) receptors, the Y4 receptor (Y4R) is unique as it prefers pancreatic polypeptide over NPY and peptide YY. Today, low-molecular-weight Y4R ligands are lacking, in particular antagonists. We synthesized a series of peptidic NPY Y4R ligands, derived from the hexapeptide acetyl-Arg-Tyr-Arg-Leu-Arg-Tyr-NH2 (1), reported to be a Y4R partial agonist with high affinity (pK i Y4R: 8.43). Peptide 1 was N-terminally extended as well as truncated and subjected to a d-amino acid scan, and Leu was replaced by different amino acids. Compounds were characterized by radioligand competition binding and functional studies (Cai 2+ mobilization and β-arrestin 1/2 recruitment). N-terminal truncation of 1 resulted in a tetrapeptide (Arg-Leu-Arg-Tyr-NH2), being a Y4R partial agonist with unchanged Y4R affinity (pK i: 8.47). Remarkably, replacement of Leu in 1 and in derivatives of 1 by Trp turned Y4R agonism to antagonism, giving Y4R antagonists with pK i values ≤7.57.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Section: ■ Experimental Sectionmentioning

confidence: 99%

Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

et al. 2020

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“…Any combination of these or other phenomena may be operative at any one time. Indeed, the selective ''knockout'' of specific arginyl residues by deimination has been a useful experimental tool for probing the enzymatic mechanisms of phosphorylases and phosphatases [224][225][226][227][228].…”

Section: Effects Of Deimination-mbp/protein Interactionsmentioning

confidence: 99%

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

2006

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Myelin basic protein (MBP) binds to negatively charged lipids on the cytosolic surface of oligodendrocyte membranes and is responsible for adhesion of these surfaces in the multilayered myelin sheath. The pattern of extensive post-translational modifications of MBP is dynamic during normal central nervous system (CNS) development and during myelin degeneration in multiple sclerosis (MS), affecting its interactions with the myelin membranes and with other molecules. In particular, the degree of deimination (or citrullination) of MBP is correlated with the severity of MS, and may represent a primary defect that precedes neurodegeneration due to autoimmune attack. That the degree of MBP deimination is also high in early CNS development indicates that this modification plays major physiological roles in myelin assembly. In this review, we describe the structural and functional consequences of MBP deimination in healthy and diseased myelin.

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“…The crystal structure of truncated γ shows these Glu residues are located in a flexible region near the substrate binding site (17). Therefore, we predicted that one or more of these acidic residues might be able to interact with Arg 16 (36). To test this possibility, three charge-reversal mutations of γ(1-300) were constructed: E61K, E62K, and E65K.…”

Section: Resultsmentioning

confidence: 99%

Site-Directed Mutants of Glycogen Phosphorylase Are Altered in Their Interaction with Phosphorylase Kinase^,

2000

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Glycogen phosphorylase is found in resting muscle as phosphorylase b, which is inactive without AMP. Phosphorylation by phosphorylase kinase (PhK) produces phosphorylase a, which is active in the absence of AMP. PhK is the only kinase that can phosphorylate phosphorylase b, which in turn is the only physiological substrate for PhK. We have explored the reasons for this specificity and how these two enzymes recognize each other by studying site-directed mutants of glycogen phosphorylase. All mutants were assayed for changes in their interaction with a truncated form of the catalytic subunit of phosphorylase kinase, gamma(1-300). Five mutations (R69K, R69E, R43E, R43E/R69E, and E501A), made at sites that interact with the amino terminus in either phosphorylase b or a, showed little difference in phosphorylation by gamma(1-300) compared to wild-type phosphorylase b. Five mutations, made at three sites in the amino-terminal tail of phosphorylase (K11A, K11E, I13G, R16A, and R16E), however, produced decreases in catalytic efficiency for gamma(1-300), compared to that for phosphorylase b. R16E was the poorest substrate for gamma(1-300), giving a 47-fold decrease in catalytic efficiency. The amino terminus, and especially Arg 16, are very important factors for recognition of phosphorylase by gamma(1-300). A specific interaction between Lys 11 of phosphorylase and Glu 110 of gamma(1-300) was also confirmed. In addition, I13G and R16A were able to be phosphorylated by protein kinase A, which does not recognize native phosphorylase.

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Arginine to citrulline replacement in substrates of phosphorylase kinase

Cited by 3 publications

References 11 publications

Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Site-Directed Mutants of Glycogen Phosphorylase Are Altered in Their Interaction with Phosphorylase Kinase^,

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Arginine to citrulline replacement in substrates of phosphorylase kinase

Cited by 3 publications

References 11 publications

Oligopeptides as Neuropeptide Y Y4 Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

Oligopeptides as Neuropeptide Y Y4 Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

A Tale of Two Citrullines—Structural and Functional Aspects of Myelin Basic Protein Deimination in Health and Disease

Site-Directed Mutants of Glycogen Phosphorylase Are Altered in Their Interaction with Phosphorylase Kinase,

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Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

Oligopeptides as Neuropeptide Y Y₄ Receptor Ligands: Identification of a High-Affinity Tetrapeptide Agonist and a Hexapeptide Antagonist

Site-Directed Mutants of Glycogen Phosphorylase Are Altered in Their Interaction with Phosphorylase Kinase^,