Strengths of Hydrogen Bonds Involving Phosphorylated Amino Acid Side Chains

Mandell, Daniel J.; Chorny, Ilya; Groban, Eli S.; Wong, Sergio E.; Levine, Elisheva; Rapp, Chaya S.; Jacobson, Matthew P.

doi:10.1021/ja063019w

Cited by 121 publications

(144 citation statements)

References 72 publications

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“…In all simulations of the non-phosphorylated CLASP2 peptide bound to EB1, conserved arginine residues in CLASP2 formed bidentate salt bridges preferentially with glutamate residues near the unstructured C terminus of EB1. Such coplanar arginine-glutamate (R-E) salt bridges are geometrically and energetically highly favorable (49). We find that lysine residues cannot substitute for arginines likely because of the less favorable lysine-glutamate hydrogen bond geometry (49), which may explain the strong conservation of these arginines in CLASPs (Fig.…”

Section: Discussionmentioning

confidence: 86%

Multisite Phosphorylation Disrupts Arginine-Glutamate Salt Bridge Networks Required for Binding of Cytoplasmic Linker-associated Protein 2 (CLASP2) to End-binding Protein 1 (EB1)

Kumar

Chimenti

Pemble

et al. 2012

Journal of Biological Chemistry

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Background: EB1-recruited microtubule ϩTIP proteins mediate microtubule functions in interphase and mitosis. Results: CLASP2 binding to EB1 requires electrostatic interactions that are inhibited by CDK-and GSK3-mediated multisite phosphorylation, and CLASP2 plus-end-tracking is switched off during mitosis. Conclusion: Arginine-glutamate salt bridges contribute considerably to the binding energy between CLASP2 and EB1. Significance: Multisite phosphorylation may be a general mechanism by which interactions of intrinsically disordered proteins are controlled.

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Section: Discussionmentioning

confidence: 86%

Multisite Phosphorylation Disrupts Arginine-Glutamate Salt Bridge Networks Required for Binding of Cytoplasmic Linker-associated Protein 2 (CLASP2) to End-binding Protein 1 (EB1)

Kumar

Chimenti

Pemble

et al. 2012

Journal of Biological Chemistry

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“…The second slowest process of pKID is also an order of magnitude slower than the slowest process observed in KID. To assess whether that slowdown in conformational kinetics was specific of the phosphate, we mutated the serine 133 to glutamate to partially mimic the negatively charged phosphate group 27 . The slowest process in gKID was found well below that of pKID (Table 1).…”

Section: Resultsmentioning

confidence: 99%

“…Regulation of binding affinity is mostly ascribed to phosphate electrostatic and hydrogen bonding interactions with KIX. However, mutation of serine 133 to a negatively charged residue such as glutamate (often considered to mimic interactions with amide NH, lysine and arginine residues 27 ) cannot recapitulate pKID activity 28 .…”

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confidence: 99%

Kinetic modulation of a disordered protein domain by phosphorylation

2014

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Phosphorylation is a major post-translational mechanism of regulation that frequently targets disordered protein domains, but it remains unclear how phosphorylation modulates disordered states of proteins. Here we determine the kinetics and energetics of a disordered protein domain the kinase-inducible domain (KID) of the transcription factor CREB and that of its phosphorylated form pKID, using high-throughput molecular dynamic simulations. We identify the presence of a metastable, partially ordered state with a 60-fold slowdown in conformational kinetics that arises due to phosphorylation, kinetically stabilizing residues known to participate in an early binding intermediate. We show that this effect is only partially reconstituted by mutation to glutamate, indicating that the phosphate is uniquely required for the long-lived state to arise. This mechanism of kinetic modulation could be important for regulation beyond conformational equilibrium shifts.

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“…In particular, the phosphate group is well suited for interacting with the guanidino group of Arg, which has a rigid, planar structure that can make directed hydrogen bonds to the doubly charged phosphate group at physiological pH. Because of the higher density of negative charge and the larger hydrated shell, phosphoamino acids form stronger and more stable hydrogen bonds and salt bridges than do Asp or Glu with Arg [8]. In this manner, a single phosphate is able to exert either intraor intermolecular effects.…”

Section: Why Is Protein Phosphorylation So Important?mentioning

confidence: 99%

Why nature chose phosphate to modify proteins

Hunter

2012

Phil. Trans. R. Soc. B

343

283

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The advantageous chemical properties of the phosphate ester linkage were exploited early in evolution to generate the phosphate diester linkages that join neighbouring bases in RNA and DNA (Westheimer 1987 Science 235, 1173 -1178. Following the fixation of the genetic code, another use for phosphate ester modification was found, namely reversible phosphorylation of the three hydroxyamino acids, serine, threonine and tyrosine, in proteins. During the course of evolution, phosphorylation emerged as one of the most prominent types of post-translational modification, because of its versatility and ready reversibility. Phosphoamino acids generated by protein phosphorylation act as new chemical entities that do not resemble any natural amino acid, and thereby provide a means of diversifying the chemical nature of protein surfaces. A protein-linked phosphate group can form hydrogen bonds or salt bridges either intra-or intermolecularly, creating stronger hydrogen bonds with arginine than either aspartate or glutamate. The unique size of the ionic shell and charge properties of covalently attached phosphate allow specific and inducible recognition of phosphoproteins by phosphospecific-binding domains in other proteins, thus promoting inducible protein-protein interaction. In this manner, phosphorylation serves as a switch that allows signal transduction networks to transmit signals in response to extracellular stimuli.Keywords: phosphate; ester; protein; phosphorylation; kinase; evolution PHOSPHATE ESTERS HAVE ADVANTAGEOUS CHEMICAL PROPERTIES FOR THE EVOLUTION OF LIFEPhosphate-containing molecules are essential constituents of all living cells. What then are the special properties of phosphate that led to its selection as a key building block during the evolution of self-replicating life forms? Phosphorus is a Group 15 element, and therefore has five electrons in its outer shell. By donating its electrons, phosphorus can form five covalent bonds; for example, by combining with four oxygen atoms, phosphorus forms orthophosphate, PO 3À 4 . Phosphate has three pKas (2.2, 7.2 (5.8 as an ester) and 12.4) and is highly soluble in water, forming a large hydrated ionic shell. Phosphate is chemically versatile and can form mono-, di-and tri-esters with alkyl and aryl hydroxyl groups, as well as acid anhydrides. In addition, phosphorus can form P-N (phosphoramidate), P-S (phosphorothioate) and P-C (phosphonate) linkages.Phosphate salts are very abundant on the Earth, and, owing to their water solubility, were readily available during the evolution of life. The ability of phosphate to form esters and anhydrides that are stable at ambient temperatures in water made it ideal for the generation of biological molecules. Phosphate esters and anhydrides predominate in living organisms, but phosphoramidates, phosphorothioates and phosphonates are all found in nature. Phosphate esters are readily formed under physiological conditions using adenosine triphosphate (ATP), a phosphate anhydride, as a phosphate donor and an enzyme catalyst. On...

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Strengths of Hydrogen Bonds Involving Phosphorylated Amino Acid Side Chains

Cited by 121 publications

References 72 publications

Multisite Phosphorylation Disrupts Arginine-Glutamate Salt Bridge Networks Required for Binding of Cytoplasmic Linker-associated Protein 2 (CLASP2) to End-binding Protein 1 (EB1)

Multisite Phosphorylation Disrupts Arginine-Glutamate Salt Bridge Networks Required for Binding of Cytoplasmic Linker-associated Protein 2 (CLASP2) to End-binding Protein 1 (EB1)

Kinetic modulation of a disordered protein domain by phosphorylation

Why nature chose phosphate to modify proteins

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