Phosphorylated residue

The RTK activity phosphorylates tyrosine residues within the intracellular domain of the receptor. These phosphorylated residues function as docking sites for proteins that will convey the signal to downstream signal transduction components. PKI can be developed that bind these phosphorylated docking sites in order to abrogate inappropriate downstream signalling. 

The alternating exposure of C3 (Leu " ) or T3 (Arg ) in the E form and Ti (Arg" ) in the E2 form reflects that motion within the segment (Mr= 18 170) between these bonds including the phosphorylated residue (Asp ) is an important element in E1-E2 transition. This is illustrated by the widely different consequences of selective cleavage of C3 and Tj for E E2 transition and cation exchange. 

The isomerism existing between the pairs of nucleotides was attributed to the different locations of the phosphoryl residues in the carbohydrate part of the parent nucleoside,49 63 since, for instance, the isomeric adenylic acids are both hydrolyzed by acids to adenine, and by alkalis or kidney phosphatase to adenosine. Neither is identical with adenosine 5-phosphate since they are not deaminated by adenylic-acid deaminase,68 60 and are both more labile to acids than is muscle adenylic acid. An alternative explanation of the isomerism was put forward by Doherty.61 He was able, by a process of transglycosidation, to convert adenylic acids a" and 6 to benzyl D-riboside phosphates which were then hydrogenated to optically inactive ribitol phosphates. He concluded from this that both isomers are 3-phosphates and that the isomerism is due to different configurations at the anomeric position. This evidence is, however, open to the same criticism detailed above in connection with the work of Levene and coworkers. Further work has amply justified the original conclusion regarding the nature of the isomerism, since it has been found that, in all four cases, a and 6 isomers give rise to the same nucleoside on enzymic hydrolysis.62 62 63 It was therefore evident that the isomeric nucleotides are 2- and 3-phosphates, since they are demonstrably different from the known 5-phosphates. The decision as to which of the pair is the 2- and which the 3-phosphate proved to be a difficult one. The problem is complicated by the fact that the a and b" nucleotides are readily interconvertible.64,64... 

The position was somewhat clarified by the isolation of 2- and 3-O-phos-phonucleosides from ribonucleic acid hydrolyzates in 92 to 100% yields,134 and also by the demonstration that 5-O-phosphonucleosides are also present in enzymic digests.49, 197 Yet this information gave no indication of the nature of the alkali-labile linkages. Thus, while the majority of the experimental evidence pointed to the phosphoryl residues as being doubly esterified with adjacent nucleosides, two facts remained apparently inexplicable on the basis of this type of structure. First, ready fission by alkalis, and secondly, the absence of 5-phosphates from alkaline hydrolyzates and their presence in enzymic digests. Both these facts have been explained by Brown and Todd in the following way.92... 

A method has been developed which is designed to remove nucleotide residues singly from a polynucleotide chain, and it is anticipated that more precise information will shortly be forthcoming regarding the order in which the nucleotides are linked.220 The method is based on the fact that esters of 3-oxo alcohols are unstable toward alkali. In agreement with this, it is found that the products of the action of periodate on adenosine 5-phosphate (XXX) or adenosine 5-(benzyl hydrogen phosphate) are hydrolyzed under very mild conditions. Thus, after removal of terminal, singly-esterified phosphoryl residues from a polynucleotide chain, it is anticipated that periodate oxidation and hydrolysis will result in the removal of the... 

It has been pointed out521 that, in a polynucleotide chain built up by esterification at the 3- and 5-positions, there are at least two possible ways in which the chain may be terminated with a singly-bound phosphoryl residue, as shown diagrammatically in XXXI and XXXII. According to... 

Alternative methods to MS for the analysis of protein phosphorylation would involve immunoaffinity techniques using antibodies specific for phosphorylated residues. Surface plasmon resonance technology has been recently used for the determination of active concentration of phosphotyrosine-containing proteins at picomolar levels.117... 

Recent studies have demonstrated that histone H4 (SI) phosphorylation is also a key role in the response to DNA double-strand breaks, cell-cycle progression and gene expression. In particular, this modification may have important roles during mitosis and S-phase-associated events in the cell-cycle and its phosphorylation found on newly synthesized histones during S-phase. However this phosphorylated residue is a novel histone modification site, and the details of this mechanism will be made evident by future experimentation. 

The rationale behind the synthesis of phosphohomoserine-containing peptides [Hse(P)] is that this phosphorylated residue is inert to base-mediated (3-elimination and thereby may provide an interesting surrogate for the study of Ser(P)-based processes. In initial work, Boc-Hse[PO(OPh)2]-OH[21l was prepared by a simple four-step procedure but was found to be unsuitable for use in Boc-based solution synthesis due to extensive amine-mediated intramolecular dephosphorylation of the Hse[PO(OPh)2] residue during mixed anhydride coupling of its N-terminus. This side reaction was subsequently minimized through the use of Fmoc-Hse[PO(OPh)2]-OH in a Fmoc-based solid-phase approach in which the use of a large... 

Receptor desensitization may also be mediated by second-messenger feedback. For example, adrenoceptors stimulate cAMP accumulation, which leads to activation of protein kinase A protein kinase A can phosphorylate residues on receptors, resulting in inhibition of receptor function. For the B2 receptor, phosphorylation occurs on serine residues both in the third cytoplasmic loop and in the carboxyl terminal tail of the receptor. Similarly, activation of protein kinase C by Gq-coupled receptors may lead to phosphorylation of this class of G protein-coupled receptors. This second-messenger feedback mechanism has been termed heterologous desensitization because activated protein kinase A or protein kinase C may phosphorylate any structurally similar receptor with the appropriate consensus sites for phosphorylation by these enzymes. 

In any reaction where the cleavage of a carbon-hydrogen bond is important, the introduction of a metal ion into the molecule in the proper position will facilitate reaction. For example, in the elimination of the elements of a phosphoric acid monoester from the molecule below, the electrostatic attraction of the cupric ion facilitates removal of the proton on the o -carbon atom with subsequent elimination of the phosphoryl residue (8). 

Phosphorylation is the most common type of regulatory modification one-third to one-half of all proteins in a eukaryotic cell are phosphorylated. Some proteins have only one phosphorylated residue, others have several, and a few have dozens of sites for phosphorylation. This mode of covalent modification is central to a large number of regulatory pathways, and we therefore discuss it in considerable detail. 

Protein kinase Consensus sequence and phosphorylated residue ... 

Many of the signaling protein kinases, including PKA, PKC, PKG, and members of the MAPK cascade, phosphorylate Ser or Thr residues in their target proteins, which in some cases acquire the ability to interact with partner proteins through the phosphorylated residue, triggering a downstream process. An alphabet soup of domains that bind (P)-Ser or (P)-Thr residues has been identified, and more are sure to be found. Each domain favors a certain sequence around the phosphorylated residue, so the domains represent families of highly specific recognition sites, able to bind to a specific subset of phosphorylated proteins. 

Many signaling proteins have domains that bind phosphorylated Tyr, Ser, or Thr residues in other proteins the binding specificity for each domain is determined by sequences that adjoin the phosphorylated residue. 

Studies on the transferase action of milk and intestinal phosphatases have shown that compounds such as glucose, glycerol, and propanediol can accept a phosphoryl residue from a wide variety of donors (IBS). The overall reaction is therefore transfer of a phosphoryl group from a donor of type (II) where X is F, 0, S, or N and R is H or an alkyl substituent, etc., or may even be absent, to an acceptor of type R —OH... 

In contrast to the lack of specificity with respect to the nonphosphoryl part of the substrate or acceptor is the strict specificity for the phosphoryl residue. Phosphodiesters and triesters are not hydrolyzed nor are mixed esters of types (III) and (IV) 124). 

As discussed above, one of the two phosphoryl groups present in lipid A is linked to the glycosidic hydroxyl group of the reducing glucosamine residue in the disaccharide. The location of the second phosphoryl residue was identified in the following way... 

In summary, these data show that Salmonella lipid A contains a 2-amino-6-0-(2-amino-2-deoxy-B-D-glucopyranosyl)-2-deoxy-D-glu-cose unit which carries phosphoryl residues in position 1 and 4, the glycosyl phosphate being a-linked (37). This structure is called the lipid A backbone. 

The irreversible inhibition of cholinesterases by organic phosphorus compounds and demonstration of the fact that a phosphoryl residue of the form (ltO)2P+ combines with the enzyme opened a new approach to the... 

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