ABSTRACT
[This corrects the article DOI: 10.1371/journal.pone.0152611.].
ABSTRACT
Phosphorylation, a critical mechanism in biological systems, is estimated to be indispensable for about 30% of key biological activities, such as cell cycle progression, migration, and division. It is synergistically balanced by kinases and phosphatases, and any deviation from this balance leads to disease conditions. Pathway or biological activity-based abnormalities in phosphorylation and the type of involved phosphatase influence the outcome, and cause diverse diseases ranging from diabetes, rheumatoid arthritis, and numerous cancers. Protein tyrosine phosphatases (PTPs) are of prime importance in the process of dephosphorylation and catalyze several biological functions. Abnormal PTP activities are reported to result in several human diseases. Consequently, there is an increased demand for potential PTP inhibitory small molecules. Several strategies in structure-based drug designing techniques for potential inhibitory small molecules of PTPs have been explored along with traditional drug designing methods in order to overcome the hurdles in PTP inhibitor discovery. In this review, we discuss druggable PTPs and structure-based virtual screening efforts for successful PTP inhibitor design.
Subject(s)
Drug Evaluation, Preclinical , Enzyme Inhibitors/pharmacology , Phosphorylation/physiology , Protein Tyrosine Phosphatases/drug effects , Protein Tyrosine Phosphatases/physiology , Catalytic Domain , Diabetes Mellitus/drug therapy , Disease , Drug Delivery Systems , Drug Design , Drug Discovery , Enzyme Inhibitors/chemistry , Humans , Models, Molecular , Molecular Docking Simulation , Neoplasms/drug therapy , Phosphoric Monoester Hydrolases/physiology , Phosphotransferases/physiology , Protein Conformation , Protein Tyrosine Phosphatase, Non-Receptor Type 1/drug effects , Protein Tyrosine Phosphatase, Non-Receptor Type 1/physiology , Protein Tyrosine Phosphatases/chemistry , Protein Tyrosine Phosphatases/classificationABSTRACT
Myotubularin-related protein 1 (MTMR1) is a phosphatase that belongs to the tyrosine/dual-specificity phosphatase superfamily. MTMR1 has been shown to use phosphatidylinositol 3-monophosphate (PI(3)P) and/or phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2) as substrates. Here, we determined the crystal structure of human MTMR1. The refined model consists of the Pleckstrin homology (PH)-GRAM and phosphatase (PTP) domains. The overall structure was highly similar to the previously reported MTMR2 structure. Interestingly, two phosphate molecules were coordinated by strictly conserved residues located in the C(X)5R motif of the active site. Additionally, our biochemical studies confirmed the substrate specificity of MTMR1 for PI(3)P and PI(3,5)P2 over other phosphatidylinositol phosphates. Our structural and enzymatic analyses provide insight into the catalytic mechanism and biochemical properties of MTMR1.
Subject(s)
Protein Tyrosine Phosphatases, Non-Receptor/chemistry , Amino Acid Sequence , Catalytic Domain , Crystallography, X-Ray , Humans , Molecular Sequence Data , Phosphatidylinositol Phosphates/metabolism , Protein Structure, Tertiary , Protein Tyrosine Phosphatases, Non-Receptor/genetics , Protein Tyrosine Phosphatases, Non-Receptor/metabolism , Recombinant Proteins/biosynthesis , Recombinant Proteins/chemistry , Recombinant Proteins/isolation & purification , Sequence Alignment , Substrate SpecificityABSTRACT
USP7 is a deubiquitinating enzyme that involves the ubiquitin proteasome system (UPS) to maintain regulation of protein synthesis and degradation. The well-known substrate of USP7 is the Mdm2-p53 complex. In fact, several studies have reported that functional inhibition of USP7 induces cancer cell apoptosis through activation of p53. However, the contribution of oxidative or endoplasmic reticulum (ER) stress, which is commonly induced by inhibition of the UPS for USP7 inhibitor-mediated apoptosis in cancer cells, has not been investigated. In contrast to previous reports, we show that p53 is not critical during USP7 inhibitor-induced apoptosis in several cancer cells. Inhibition of deubiquitinating enzyme activities by USP7 inhibitors causes ER stress by accumulating polyubiquitinated proteins in cancer cells. Furthermore, we demonstrate that USP7 inhibitors increase intracellular reactive oxygen species and mainly cause cancer cell apoptosis. Taken together, our results reveal that oxidative and ER stress, rather than the Mdm2-p53 axis, mainly contributes to USP7 inhibitor-mediated apoptosis in cancer cells.
Subject(s)
Antineoplastic Agents/administration & dosage , Apoptosis/drug effects , Endoplasmic Reticulum Stress/drug effects , Neoplasms, Experimental/metabolism , Oxidative Stress/drug effects , Ubiquitin Thiolesterase/metabolism , Cell Line, Tumor , Humans , Neoplasms, Experimental/drug therapy , Neoplasms, Experimental/pathology , Reactive Oxygen Species/metabolism , Ubiquitin Thiolesterase/antagonists & inhibitors , Ubiquitin-Specific Peptidase 7 , Ubiquitination/drug effectsABSTRACT
RNA polymerase II carboxyl-terminal domain (pol II CTD) phosphatases are a newly emerging family of phosphatases that are members of DXDX (T/V). The subfamily includes Small CTD phosphatases, like SCP1, SCP2, SCP3, TIMM50, HSPC129 and UBLCP. Extensive study of SCP1 has elicited the diversified roles of the small C terminal domain phosphatase. The SCP1 plays a vital role in various biological activities, like neuronal gene silencing and preferential Ser5 dephosphorylation, acts as a cardiac hypertrophy inducer with the help of its intronic miRNAs, and has shown a key role in cell cycle regulation. This short review offers an explanation of the mechanism of action of small CTD phosphatases, in different biological activities and metabolic processes.
