Three protein kinase structures define a common motif

Taylor, Susan S.; Radzio‐Andzelm, Elzbieta

doi:10.1016/s0969-2126(00)00036-8

Cited by 362 publications

(321 citation statements)

References 44 publications

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“…Significant effort has also been invested into structural and mechanistic studies (Adams, 2001 ;Taylor & Kornev, 2011 ;Zhang, 2003). There are more than 500 protein kinases encoded in the human genome, representing one of the largest protein families (Manning et al 2002), and, despite sequence and structural diversity, many share nearly conserved catalytic domains (Taylor & Radzio-Andzelm, 1994). The chemical steps in some kinases are discussed in Section 4.5.3, and here, we would only like to comment that the details of the transfer of allosteric information from the effector binding site on one side of the membrane to the phosphorylation site is still a remarkable puzzle.…”

Section: Other Signal Transducing Systemsmentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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Phosphoryl transfer plays key roles in signaling, energy transduction, protein synthesis, and maintaining the integrity of the genetic material. On the surface, it would appear to be a simple nucleophile displacement reaction. However, this simplicity is deceptive, as, even in aqueous solution, the low-lying d-orbitals on the phosphorus atom allow for eight distinct mechanistic possibilities, before even introducing the complexities of the enzyme catalyzed reactions. To further complicate matters, while powerful, traditional experimental techniques such as the use of linear free-energy relationships (LFER) or measuring isotope effects cannot make unique distinctions between different potential mechanisms. A quarter of a century has passed since Westheimer wrote his seminal review, ‘Why Nature Chose Phosphate’ (Science 235 (1987), 1173), and a lot has changed in the field since then. The present review revisits this biologically crucial issue, exploring both relevant enzymatic systems as well as the corresponding chemistry in aqueous solution, and demonstrating that the only way key questions in this field are likely to be resolved is through careful theoretical studies (which of course should be able to reproduce all relevant experimental data). Finally, we demonstrate that the reason that naturereallychose phosphate is due to interplay between two counteracting effects: on the one hand, phosphates are negatively charged and the resulting charge-charge repulsion with the attacking nucleophile contributes to the very high barrier for hydrolysis, making phosphate esters among the most inert compounds known. However, biology is not only about reducing the barrier to unfavorable chemical reactions. That is, the same charge-charge repulsion that makes phosphate ester hydrolysis so unfavorable also makes it possible to regulate, by exploiting the electrostatics. This means that phosphate ester hydrolysis can not only be turned on, but also be turned off, by fine tuning the electrostatic environment and the present review demonstrates numerous examples where this is the case. Without this capacity for regulation, it would be impossible to have for instance a signaling or metabolic cascade, where the action of each participant is determined by the fine-tuned activity of the previous piece in the production line. This makes phosphate esters the ideal compounds to facilitate life as we know it.

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Section: Other Signal Transducing Systemsmentioning

confidence: 99%

Why nature really chose phosphate

Kamerlin

Sharma

Prasad

et al. 2013

Quart. Rev. Biophys.

340

448

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“…Similarly, the E58G mutant of Cdc28p can bind Cln2p to 60% of the wild-type level, but Cln2-associated kinase activity is reduced to 0.1% (Levine et al 1998). The E51 residue of Cdk2p belongs to a triad of catalytic site residues (K33, E51 and D145) that are conserved among eukaryotic Cdks, including Pho85p (Taylor & Rudzio-Andzelm 1994). The triad is involved in the ATP phosphate orientation and is essential for catalysis (Jeffrey et al 1995).…”

Section: Different Residues May Be Required For Different Cyclin Bindingmentioning

confidence: 99%

The Pho85 kinase, a member of the yeast cyclin‐ dependent kinase (Cdk) family, has a regulation mechanism different from Cdks functioning throughout the cell cycle

et al. 1999

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Background: The PHO85 gene is a negative regulator of the PHO system in the yeast Saccharomyces cerevisiae and encodes a protein kinase (Pho85p) which is highly homologous to the Cdc28 kinase (Cdc28p). Although the two kinases share a 51% identity and their functional domains are well conserved, PHO85 fails to replace CDC28. Pho85p forms complexes with G 1 -cyclin homologues, including Pcl1p, Pcl2p and Pcl9p, and is thought to be involved in the cell-cycle regulation at G 1 and the end of M. By analysing the genetic and biochemical properties of Pho85p, we studied whether the regulation of Pho85p activity is similar to other cyclin-dependent kinases (Cdks) directly involved in cell cycle regulation.

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“…The portion of CKII present in both clones was the carboxy-terminal 176 amino acids of the ~ subunit, which includes approximately half of the highly conserved core present in most Ser/Thr kinases (Saxena et al 1987). On the basis of the crystal structures of related kinases (Taylor and Radzio-Andzelm 1994) this portion of CKII includes the binding pocket for a peptide inhibitor, and therefore contains a significant part of the substrate binding site (Knighton et al 1991a,b).…”

Section: R E S U L T Smentioning

confidence: 99%

A role for phosphorylation by casein kinase II in modulating Antennapedia activity in Drosophila.

Jaffe

Ryoo²,

Mann³

1997

Genes Dev.

114

101

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We present evidence that the in vivo activity of the HOX protein Antennapedia (ANTP) is modified because of phosphorylation by the serine/threonine kinase casein kinase II (CKII). Using an in vivo assay a form of ANTP that has alanine substitutions at its CKII target sites has, in addition to wild-type ANTP functions, the ability to alter severely thoracic and abdominal development. The novel functions of this protein suggest that this form of ANTP is not suppressed phenotypicaUy by the more posterior homeotic proteins. In contrast, the in vivo activity of a form of ANTP that contains acidic amino acid substitutions at its CKII target sites, thereby mimicking a constitutively phosphorylated ANTP protein, is greatly reduced. This hypoactive form of ANTP, but not the alanine-substituted form, is also reduced in its ability to bind to DNA cooperatively with the homeodomain protein Extradenticle. Our results suggest that phosphorylation of ANTP by CKII is important for preventing inappropriate activities of this homeotic protein during embryogenesis.

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Three protein kinase structures define a common motif

Cited by 362 publications

References 44 publications

Why nature really chose phosphate

Why nature really chose phosphate

The Pho85 kinase, a member of the yeast cyclin‐ dependent kinase (Cdk) family, has a regulation mechanism different from Cdks functioning throughout the cell cycle

A role for phosphorylation by casein kinase II in modulating Antennapedia activity in Drosophila.

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