SHP Family Protein Tyrosine Phosphatases Adopt Canonical Active-Site Conformations in the Apo and Phosphate-Bound States

Alicea-Velázquez, Nilda L.; Boggon, Titus J.

doi:10.2174/09298665113209990041

Cited by 11 publications

(18 citation statements)

References 45 publications

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“…3b). An upstream acidic residue, E/ D, and a conserved proline are present in BacA/UppP, similar to the WPD loop in PTEN that transitions from an 'open' to a 'closed' state, optimally placing the catalytic acidic residue (E/D) in a favourable position to facilitate substrate dephosphorylation (Alicea-Velazquez & Boggon, 2013;Barr et al, 2009;Zhang & Bishop, 2008). The WPD and P loop regions are completely conserved for BacA/UppP homologues in Gram-negative bacteria (Fig.…”

Section: Baca/uppp: the Principal Undecaprenyl Pyrophosphate Phosphatmentioning

confidence: 98%

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Bickford

Nick

2013

Microbiology

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Isoprenoid lipid carriers are essential in protein glycosylation and bacterial cell envelope biosynthesis. The enzymes involved in their metabolism (synthases, kinases and phosphatases) are therefore critical to cell viability. In this review, we focus on two broad groups of isoprenoid pyrophosphate phosphatases. One group, containing phosphatidic acid phosphatase motifs, includes the eukaryotic dolichyl pyrophosphate phosphatases and proposed recycling bacterial undecaprenol pyrophosphate phosphatases, PgpB, YbjB and YeiU/LpxT. The second group comprises the bacterial undecaprenol pyrophosphate phosphatase, BacA/UppP, responsible for initial formation of undecaprenyl phosphate, which we predict contains a tyrosine phosphate phosphatase motif resembling that of the tumour suppressor, phosphatase and tensin homologue (PTEN). Based on protein sequence alignments across species and 2D structure predictions, we propose catalytic and lipid recognition motifs unique to BacA/UppP enzymes. The verification of our proposed active-site residues would provide new strategies for the development of substratespecific inhibitors which mimic both the lipid and pyrophosphate moieties, leading to the development of novel antimicrobial agents.

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Section: Baca/uppp: the Principal Undecaprenyl Pyrophosphate Phosphatmentioning

confidence: 98%

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Bickford

Nick

2013

Microbiology

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“…Depois de rompida a auto-inibição através da interação de uma molécula ativadora em algum dos dois sítios do domínio SH2, há uma alteração na conformação da enzima que possibilita a entrada do substrato no domínio catalítico da PTP, onde ocorre a reação de desfosforilação (Figura 6). 19,20 Figura 6. Auto inibição da PTP através do domínio SH2, ativação e interação com o substrato 8 Estas enzimas estão localizadas no citoplasma e possuem papel regulatório em citocinas e na sinalização de fatores de crescimento.…”

Section: Proteínas Tirosina Fosfatases Da Família Shpunclassified

Protein Tyrosine Phosphatase SHP-2 and its Relation with Cancer

2017

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This paper presents an introduction to the cellular signaling mechanism governed by the balanced action of protein tyrosine kinases (PTK) and protein tyrosine phosphatases (PTP) by phosphorylation / dephosphorylation of tyrosine residues in proteins. For many years PTK were the main targets for the development of anticancer drugs and today many PTK inhibitors are already widely used in the cancer treatment. Inhibitors of PTP are still in the development stage because of misconceptions about this family of enzymes. Thus, this review seeks to clarify some important points that justify the current interest in PTP as a target in cancer treatment. An introductory description of the classification is made, together with a discussion on structure and PTP mechanism of action with particular focus on SHP family composed of two PTP: SHP-1 and SHP-2. This paper discusses the effects of over expression or gain of function mutations occurred in SHP-2 in the emergence and progression of cancerous state by activation of the RAS / ERK. Finally, some SHP-2 inhibitors that have been discovered to date are presented.

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“…Note that the amino-acid numbering of the SHP-1 and FAP-1 PTP domains is highly divergent because the two proteins include different complements of non-catalytic domains N-terminal to their homologous PTP domains. (B) Three-dimensional structure of SHP-1’s catalytic domain (PDB ID: 4hjp) [13]. SHP-1 is shown as a ribbon, with the PTP loop colored yellow and the flanking β-strand and α-helix colored green and blue, respectively.…”

Section: Figurementioning

confidence: 99%

“…The hydrophobic side chain of Val451 extends from a β-strand (Figure 1B) to pack against side chains that are presented from a nearby α-helix [13]. The relative spacing of these two secondary structural elements helps to determine the position of the catalytically critical PTP loop [14], and it possible that a larger methionine side chain would not be tolerated at the 451 position.…”

Section: Introductionmentioning

confidence: 99%

A missense methionine mutation augments catalytic activity but reduces thermal stability in two protein tyrosine phosphatases

Bishop

2016

Biochemical and Biophysical Research Communications

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Recent data sets that catalog the missense mutations in thousands of human genomes have revealed a vast and largely unexplored world of non-canonical protein sequences that are expressed in humans. The functional consequences of most human missense mutations, however, are unknown, and the accuracy with which their effects can be predicted by computational algorithms remains unclear. Among humans of European descent, the most common missense mutation in the catalytic domain of SH2-containing protein tyrosine phosphatase 1 (SHP-1) converts the enzyme’s canonical valine 451 to methionine (V451M). The V451M mutation lies in a conserved motif adjacent to the protein tyrosine phosphatase (PTP) consensus sequence and is predicted to compromise catalytic function. In this study it is shown that, counter to prediction, V451M SHP-1 possesses increased catalytic activity as compared to the wild-type enzyme. Additionally, a PTP-wide search of missense-mutation data revealed a variant of one other PTP, Fas-associated PTP (FAP-1), that contains a methionine mutation at the position corresponding to 451 of SHP-1 (T2406M FAP-1). It is shown here that the T2406M mutation increases FAP-1’s PTP activity, to a degree that is comparable to the activation deriving from the V451M mutation in SHP-1. Although the two non-canonical methionine residues confer increased activity at moderate temperatures, both V451M SHP-1 and T2406M FAP-1 are less thermally stable than their canonical counterparts, as demonstrated by the mutants’ strongly reduced activities at high temperatures. These results highlight the challenges in predicting the functional consequences of missense mutations, which can differ under varying conditions, and suggest that, with regard to position 451/2406, canonical PTP domains have “chosen” stability over optimized activity during the course of evolution.

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SHP Family Protein Tyrosine Phosphatases Adopt Canonical Active-Site Conformations in the Apo and Phosphate-Bound States

Cited by 11 publications

References 45 publications

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Conservation of the PTEN catalytic motif in the bacterial undecaprenyl pyrophosphate phosphatase, BacA/UppP

Protein Tyrosine Phosphatase SHP-2 and its Relation with Cancer

A missense methionine mutation augments catalytic activity but reduces thermal stability in two protein tyrosine phosphatases

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