THR-18 / D-Pharm - LARVOL DELTA

Kinetic Scheme of Myosin Phosphorylation by ZIP Kinase. (PubMed, Biochemistry) - "We found that ZIPK phosphorylates MRLC sequentially, first at Ser19 and then at Thr18, determined by quantitative mass spectrometry analysis on wild-type MRLC...By incorporating the kinetic and dissociation constants obtained from mutant analysis and cosedimentation assays, respectively, a simple kinetic model reasonably well reproduced the time courses of phosphorylation for both isolated MRLC and SMM. This provides systemic insight into the regulatory mechanism of myosin contractility by ZIPK."

Journal

A tailored phospho-p53 library probes antibody specificity and recognition limitations. (PubMed, Chembiochem) - "To address this limitation, we harness our recently developed approach for the semisynthesis of site-specifically phosphorylated p53 to generate a comprehensive library of singly phosphorylated p53 including all TAD1 sites: Ser6, Ser9, Ser15, Thr18, Ser20, Ser33 and Ser37...Our results confirm the specificity of the target site of most phosphorylation-specific anti-p53 antibodies, but also reveal wide-spread epitope masking by phosphorylation, which has implications for p53 research and diagnostics. Our library provides a toolkit to study the function of p53 phosphorylation directly and indirectly as a quality control agent for some of the most widely used reagents in the field."

Journal • Oncology

MECHANOTRANSDUCTION VIA MYOSIN II ISOFORMS CONTRIBUTES TO TGFBETA-DRIVEN FIBROBLAST ACTIVATION (SSWC 2024) - "HD fibroblasts exhibited a similar pattern of redistribution of NMII isoforms (n = 8, NMIIB filament/cytoplasm intensity median, [range] ctrl 1.2 [0.8-1.7] vs TGFb 1.9 [1.8-2.3], p = 0.02) and increased phosphorylation of MLC at Thr18/Ser19 upon TGFb stimulation (n = 8, ppMLC fluorescence intensity/cell median, [range] ctrl 10000 [8000-1200], TGFb 15000 [12000-17000], p 0.002)... Our data point to an altered actomyosin cytoskeleton dynamics and force distribution in SSc fibroblasts and indicate that NMII isoforms are a downstream mediator of the stimulatory effects of TGFb in fibroblasts."

Fibrosis • Immunology • Scleroderma • Systemic Sclerosis • IL6 • TGFB1

Ab initio modeling of human IRS1 protein to find novel target to dock with drug MH to mitigate T2DM diabetes by insulin signaling. (PubMed, 3 Biotech) - "Docking of IRS1 with drug MH demonstrated interaction of Ser-70, Thr-18, and Pro-69 with C-H bonds; Gln-71, and Glu-113 with hydrogen bonds; while both Glu-114 and Glu-113 with salt-bridge connection...SASA value of IRS1 indicated non-significant fluctuation between IRS1 and drug MH means ligand (drug) and IRS1 receptor form stable structure. Hydrogen bond strength of IRS1 and IRS1-met was 81.2 and 76.4, respectively, which suggested stable interaction."

Journal • Diabetes • Metabolic Disorders • Type 2 Diabetes Mellitus • IRS1

Markov State Model of Solvent Features Reveals Water Dynamics in Protein-Peptide Binding. (PubMed, J Phys Chem B) - "The solvent shells contributing most to the first tICA eigenvector are those centered on Lys24 and Thr18 of the p53 TAD peptide in the range of 3-6 Å. Important solvent shells were visualized to reveal solvation and desolvation transitions along the peptide-protein binding trajectories. Our results provide a solvent-centric view of the hydrophobic effect in action for a realistic peptide-protein binding scenario."

Journal

Transcriptome analysis of turbot (Scophthalmus maximus) kidney responses to inactivated bivalent vaccine against Aeromonas salmonicida and Edwardsiella tarda. (PubMed, Fish Shellfish Immunol) - "Eight DEGs (ccr10, calr, casr, mybpha, cd28, thr18, cd20a.3 and c5) were randomly selected for qRT-PCR analysis, which confirmed the validity of the RNA-seq. Our results provide valuable insight into the immune mechanism of inactivated bivalent vaccine against A. salmonicida and E. tarda in Scophthalmus maximus."

Journal • Ophthalmology • CALR • CCR10 • MYBPH

T18/S19 diphosphorylation of myosin regulatory light chain impairs pulmonary artery relaxation in monocrotaline-induced pulmonary hypertensive rats. (PubMed, Pflugers Arch) - "It has been shown that elevated RhoA-dependent kinase (ROCK) activity or decreased MLC phosphatase (MLCP) activity leads to further phosphorylation of Thr18 (T18/S19-pp), which has been linked to vasospastic diseases...Taken together, the decreased sGC and MLCP, and increased ROCK increased T18/S19-pp, which leads to the decreased ability of PA to relax in PAH-MCT rats. PA specific inhibition of ROCK or activation of MLCP are expected to serve as potential drugs in the treatment of PAH."

Journal • Preclinical • Cardiovascular • Hypertension • Pulmonary Arterial Hypertension • Pulmonary Disease • Respiratory Diseases • RHOA

Rho kinase inhibitors ameliorate cognitive impairment in a male mouse model of methamphetamine-induced schizophrenia. (PubMed, Pharmacol Res) - "Two proteins downstream of Rho kinase, myosin phosphatase-targeting subunit 1 (MYPT1; Thr696) and myosin light chain kinase 2 (MLC2; Thr18/Ser19), exhibited increased phosphorylation in the infralimbic mPFC and DMS, respectively, after METH treatment, and fasudil inhibited these increases...Oral administration of haloperidol and clozapine suppressed METH-induced hyperactivity, but fasudil had no effect. These results suggest that METH activates Rho kinase in the infralimbic mPFC and DMS, which leads to cognitive impairment in male mice. Rho kinase inhibitors ameliorate METH-induced cognitive impairment, perhaps via the cortico-striatal circuit."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Mental Retardation • Psychiatry • Schizophrenia • FOS • MYLK

Zip Kinase Is Involved in Progression of Myofibroblast Differentiation of Human Pleural Mesothelial Cells (ATS 2023) - "Interestingly, MLC phosphorylation at both Thr18 of MLC was increased and monophosphorylated MLC at Ser19 is only marginally changed... These results suggested that ZIP kinase is responsible for phosphorylation of actomysin that activates cell contractivity of HPMCs and promotes myofibroblast differentiation."

Fibrosis • Idiopathic Pulmonary Fibrosis • Immunology • Respiratory Diseases • TGFB1

Activation of p53: how phosphorylated Ser15 triggers sequential phosphorylation of p53 at Thr18 by CK1δ. (PubMed, Proteins) - "We propose that upon phosphorylation at Ser15 the p53 TAD1 peptide binds to CK1? through an electrostatically driven induced fit mechanism resulting in a flanking fuzzy complex."

Journal • MDM2

Structural modulation of p53TAD1-TAZ2 complex upon mutations and post-translational modification. (PubMed, J Biomol Struct Dyn) - "The electrostatic interactions due to different charge environment together with H-bonding and hydrophobic interaction dictate diverse binding approach between the two. The results of this computational study further explain the importance of the Thr18 as a PTM site in atomistic detail, hence shedding further light to the understanding of how PTMs are imperative for p53 activity to protect the cellular world.Communicated by Ramaswamy H. Sarma."

Journal • Oncology

Single-molecule analysis of interaction between p53TAD and MDM2 using aerolysin nanopores. (PubMed, Chem Sci) - "Notably, the addition of small-molecule PPI inhibitors, Nutlin-3 and AMG232, or Thr18 phosphorylation of p53TAD peptide, were able to diminish the extraordinarily long-lived events and restore the short-lived translocation of the peptide rescued from the complex. Taken together, our results elucidate a novel mechanism of single-molecule sensing for analyzing PPIs and their inhibitors using aerolysin nanopores. This novel methodology may contribute to remarkable improvements in drug discovery targeted against undruggable PPIs."

Journal • Oncology • MDM2