Abstract
The dual specificity phosphatase (DUSP) family has catalytically inactive members, called pseudophosphatases. They have mutations in their catalytic motifs that render them enzymatically inactive. This study analyzes the significance of two pseudophosphatases, MK-STYX [MAPK (mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding protein]) and STYX (serine/threonine/tyrosine-interacting protein), throughout their evolution and provides measurements and comparison of their evolutionary conservation. Phylogenetic trees were constructed to show any deviation from various species evolutionary paths. Data was collected on a large set of proteins that have either one of the two domains of MK-STYX, the DUSP domain or the cdc-25 homology (CH2) /rhodanese-like domain. The distance between species pairs for MK-STYX or STYX and Ka/Ks ratio were calculated. In addition, both pseudophosphatases were ranked among a large set of related proteins, including the active homologs of MK-STYX, MKP (MAPK phosphatase)-1 and MKP-3. MK-STYX had one of the highest species-species protein distances and was under weaker purifying selection pressure than most proteins with its domains. In contrast, the protein distances of STYX were lower than 82% of the DUSP-containing proteins and was under one of the strongest purifying selection pressures. However, there was similar selection pressure on the N-terminal sequences of MK-STYX, STYX, MKP-1, and MKP-3. We next perform statistical coupling analysis, a process that reveals interconnected regions within the proteins. We find that while MKP-1,-3, and STYX all have 2 functional units (sectors), MK-STYX only has one, and that MK-STYX is similar to MKP-3 in the evolutionary coupling of the active site and KIM domain. Within those two domains, the mean coupling is also most similar for MK-STYX and MKP-3. This study reveals striking distinctions between the evolutionary patterns of MK-STYX and STYX, suggesting a very specific role for each pseudophosphatase, further highlighting the relevance of these atypical members of DUSP as signaling regulators. Therefore, our study provides computational evidence and evolutionary reasons to further explore the properties of pseudophosphatases, in particular MK-STYX and STYX.
Highlights
IntroductionPseudophosphatases have emerged as critical regulators of signaling pathways[3,4]
Abbreviations API Application programming interface CD Cluster of designation CDC Cell-division cycle CDC# Cell-division cycle phosphatase with an assigned number CDK Cyclin-dependent kinase complex coding sequences (CDS) Coding sequences CH2 Cell division cycle 25 phosphatase homology 2 CSV Comma-separated values DNA Deoxyribonucleic acid dual specificity phosphatase (DUSP) Dual-specificity phosphatase or the dual-specificity phosphatase domain EMBL-EBI European Molecular Biology Laboratory – European Bioinformatics Institute ERK Extracellular signal-regulated kinases 1⁄2 ETE 3 Environment for tree exploration G3BP-1 Ras-GTPase activating protein SH3 domain binding protein-1 I-TASSER Iterative Threading ASSEmbly Refinement
ITOL Interactive Tree Of Life kinase interaction motif (KIM) Kinase interaction motif Ka Number of nonsynonymous substitutions per nonsynonymous site Ks Number of synonymous substitutions per synonymous site MAPK Mitogen-activated protein kinase MEGA Molecular evolutionary genetics analysis MEK Mitogen-activated protein kinase kinase MAPK phosphatase (MKP)# MAP kinase phosphatase with an assigned number MK-STYX Mitogen-activated protein kinase phosphoserine/threonine/tyrosine-binding mRNA Messenger ribonucleic acid MUSCLE Multiple sequence comparison by log-expectation NCBI National center for biotechnology information pERK Phospho-ERK pSer Phospho-serine pThr Phospho-threonine pTyr Phospho-tyrosine PTP Protein tyrosine phosphatase PTPM1 PTP localized to the mitochondrion REST Representational state transfer SCF SKP/Cullin1/F-box complex STYX Phosphoserine/threonine/tyrosine-interacting protein STYXL1 STYX-like-1 UniProtKB Universal protein knowledge base protein
Summary
Pseudophosphatases have emerged as critical regulators of signaling pathways[3,4]. They exert their function by serving as competitors, signaling integrators, modulators, and anchors in cellular p rocesses[3–5]. There has been an explosion of data implicating the pseudophosphatase MK-STYX [MAPK (mitogen-activated protein kinase) phosphoserine/threonine/tyrosinebinding protein] in diseases such as hepatocellular c arcinoma[7] and glioblastoma[6,8]. Pseudophosphatases roles as signaling regulators and linkage to diseases indicate their immediate importance to understanding their molecular mechanism(s). The MK-STYX protein is encoded by the gene STYXL1 (serine/threonine/tyrosine interacting like 1) and is referred to as DUSP24 (dual specificity phosphatase 24). Protein interactions and function can be inferred through comparative and evolutionary genetics, which are pursued in this manuscript. Large scale bioinformatics studies such as usage of gene clusters to infer functional coupling are imperative in understanding the molecular mechanism of pseudophosphatase[3,13]. New types of analyses and better models for calculating co-evolution and interacting networks have been developed[14], which has expanded our knowledge of the function of proteins
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