Phosphoprotein–Protein Interactions Revealed by the Crystal Structure of Kinase-Associated Phosphatase in Complex with PhosphoCDK2

Song, Haiwei; Hanlon, Neil; Brown, Nicholas R.; Noble, M.E.M.; Johnson, L.N.; Barford, David

doi:10.1016/s1097-2765(01)00208-8

Cited by 171 publications

(150 citation statements)

References 34 publications

Supporting

Mentioning

140

Contrasting

Unclassified

Order By: Relevance

“…surrounding the catalytic P-loop, the catalytic cleft of PRL-3 is the shallowest of all known phosphatases. The structure of the complex between KAP and phospho-CDK2 showed that, unlike tyrosine phosphatases, the substrate specificity of DSPs may rely on interactions distant from the active site of the catalytic domain (27). These interactions may also involve various loops, surrounding the catalytic P-loop.…”

Section: Discussionmentioning

confidence: 99%

“…The other distinct feature of the PRL-3 catalytic site is the lack of protruding loops ( Fig. 3B), which often participate in substrate binding (10,27). The N terminus, preceding strand ␤1, which is usually structured in protein-tyrosine phosphatases and contributes to substrate binding, is unstructured and mobile in PRL-3.…”

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

“…The N terminus, preceding strand ␤1, which is usually structured in protein-tyrosine phosphatases and contributes to substrate binding, is unstructured and mobile in PRL-3. The region following strand ␤2, which recognizes binding partners for KAP phosphatase (27), is much shorter and flat. The loop following strand ␤3 is also much shorter and flatter than in the PTP1B, VHR, PYST, and KAP phosphatases (10,27,28).…”

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

“…The region following strand ␤2, which recognizes binding partners for KAP phosphatase (27), is much shorter and flat. The loop following strand ␤3 is also much shorter and flatter than in the PTP1B, VHR, PYST, and KAP phosphatases (10,27,28). The resulting catalytic pocket is extremely shallow and suggests a broad range of specificity for PRL-3.…”

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

“…The disulfide bond formation between these cysteines provides another plau- sible explanation for the observed low catalytic activity. This is particularly important because a similar intramolecular disulfide bond in KAP phosphatase was extremely stable, even in the presence of 0.2 M DTT (27). Mutation of the noncatalytic cysteine residue in KAP prevented the formation of this disulfide bond and increased the enzymatic activity 40-fold.…”

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

See 4 more Smart Citations

Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3

Kozlov

Cheng

Ziomek

et al. 2004

Journal of Biological Chemistry

210

View full text Add to dashboard Cite

Phosphatases and kinases are the cellular signal transduction enzymes that control protein phosphorylation. PRL phosphatases constitute a novel class of small (20 kDa), prenylated phosphatases with oncogenic activity. In particular, PRL-3 is consistently overexpressed in liver metastasis in colorectal cancer cells and represents a new therapeutic target. Here, we present the solution structure of PRL-3, the first structure of a PRL phosphatase. The structure places PRL phosphatases in the class of dual specificity phosphatases with closest structural homology to the VHR phosphatase. The structure, coupled with kinetic studies of site-directed mutants, identifies functionally important residues and reveals unique features, differentiating PRLs from other phosphatases. These differences include an unusually hydrophobic active site without the catalytically important serine/threonine found in most other phosphatases. The position of the general acid loop indicates the presence of conformational change upon catalysis. The studies also identify a potential regulatory role of Cys 49 that forms an intramolecular disulfide bond with the catalytic Cys 104 even under mildly reducing conditions. Molecular modeling of the highly homologous PRL-1 and PRL-2 phosphatases revealed unique surface elements that are potentially important for specificity.PRL (for phosphatase of regenerating liver) phosphatases constitute a novel class of small tyrosine phosphatases involved in the modulation of cell growth. Initial studies identified PRL-1 as an intermediate-early gene expressed in the early response of regenerating liver tissue to mitogens (1). Overexpression of this protein was shown to lead to cellular transformation (1-3). The biological role of PRL-1 is tissue-dependent. Its overexpression is associated with cell proliferation in the liver (1) but with differentiation of epithelial cells in the digestive system (4). The closely related phosphatases PRL-2 and PRL-3 are also involved in growth regulation, proliferation, and cell invasion (3, 5, 6). All three proteins are prenylated at their C terminus, which critically affects their cellular localization and function (6 -8). As shown for the human PRL-2, the role of PRLs is associated with the regulation of progression through mitosis, and their cellular localization is likely controlled by the cell cycle (8).PRL phosphatases are widely distributed in eukaryotes. In humans, PRL-1 and PRL-2 are ubiquitously expressed in various tissues (6), whereas PRL-3 is normally expressed in cardiac and skeletal muscles (5). Comprising typically only 140 -180 amino acids, PRLs are among the smallest phosphatases. They consist of a single catalytic domain lacking any auxiliary docking/regulatory domains other than the prenylation site at the C terminus. PRLs contain the protein-tyrosine phosphatase (PTPase) 1 active consensus motif HCXXGXXR, referred to as the P-loop; however, their primary sequence shows only remote similarity to phosphatases in other regions. Tyrosine-specific phosphatases a...

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

Section: Solution Structure Of Prl-3-mentioning

confidence: 99%

See 3 more Smart Citations

Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3

Kozlov

Cheng

Ziomek

et al. 2004

Journal of Biological Chemistry

210

View full text Add to dashboard Cite

show abstract

Overview of Protein Structural and Functional Folds

2004

View full text Add to dashboard Cite

This overview provides an illustrated, comprehensive survey of some commonly observed protein-fold families and structural motifs, chosen for their functional significance. It opens with descriptions and definitions of the various elements of protein structure and associated terminology. Following is an introduction into web-based structural bioinformatics that includes surveys of interactive web servers for protein fold or domain annotation, protein-structure databases, protein-structure-classification databases, structural alignments of proteins, and molecular graphics programs available for personal computers. The rest of the overview describes selected families of protein folds in terms of their secondary, tertiary, and quaternary structural arrangements, including ribbon-diagram examples, tables of representative structures with references, and brief explanations pointing out their respective biological and functional significance.

show abstract

Reverse cholesterol transport in diabetes mellitus

Quintão

Medina

Passarelli

2000

Diabetes Metab. Res. Rev.

View full text Add to dashboard Cite

There are epidemiological data and experimental animal models relating the development of premature atherosclerosis with defects of the reverse cholesterol transport (RCT) system. In this regard, the plasma concentrations of the high density lipoprotein (HDL) subfractions, of cholesteryl ester transfer protein (CETP), as well as the activity of the enzyme lecithin-cholesterol acyl transferase (LCAT) play critical roles. However, there has been plenty of evidence that atherosclerosis in diabetes mellitus (DM) is ascribed to a greater arterial wall cell uptake of modified apoB-containing lipoproteins whereas a primary or predominant defect of the RCT system is still a subject of debate. In other words, in spite of the fact that in DM the composition and rates of metabolism of the HDL particles are greatly altered and display a diminished in vitro efficiency to remove cell cholesterol, definitive in vivo demonstration of the importance of this fact in atherogenesis is lacking. Furthermore, the roles played by LCAT and CETP in RCT in DM are difficult to interpret because the in vitro procedures of measurement utilized have either been inadequate, or inappropriately interpreted. Knock-out or transgenic mice are much needed models to investigate the roles of LCAT, CETP, phospholipid transfer protein (PLTP), and of a CETP inhibitor in the development of atherosclerosis of experimental DM.

show abstract

Phosphoprotein–Protein Interactions Revealed by the Crystal Structure of Kinase-Associated Phosphatase in Complex with PhosphoCDK2

Cited by 171 publications

References 34 publications

Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3

Structural Insights into Molecular Function of the Metastasis-associated Phosphatase PRL-3

Overview of Protein Structural and Functional Folds

Reverse cholesterol transport in diabetes mellitus

Contact Info

Product

Resources

About