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Direct Activation of Human MLKL by a Select Repertoire of Inositol Phosphate Metabolites.
McNamara DE, Dovey CM, Hale AT, Quarato G, Grace CR, Guibao CD, Diep J, Nourse A, Cai CR, Wu H, Kalathur RC, Green DR, York JD, Carette JE, Moldoveanu T
(2019) Cell Chem Biol 26: 863-877.e7
MeSH Terms: Animals, Cell Survival, HT29 Cells, Humans, Inositol Phosphates, Protein Kinases, Sf9 Cells, Spodoptera
Show Abstract · Added March 30, 2020
Necroptosis is an inflammatory form of programmed cell death executed through plasma membrane rupture by the pseudokinase mixed lineage kinase domain-like (MLKL). We previously showed that MLKL activation requires metabolites of the inositol phosphate (IP) pathway. Here we reveal that I(1,3,4,6)P, I(1,3,4,5,6)P, and IP promote membrane permeabilization by MLKL through directly binding the N-terminal executioner domain (NED) and dissociating its auto-inhibitory region. We show that IP and inositol pentakisphosphate 2-kinase (IPPK) are required for necroptosis as IPPK deletion ablated IP production and inhibited necroptosis. The NED auto-inhibitory region is more extensive than originally described and single amino acid substitutions along this region induce spontaneous necroptosis by MLKL. Activating IPs bind three sites with affinity of 100-600 μM to destabilize contacts between the auto-inhibitory region and NED, thereby promoting MLKL activation. We therefore uncover MLKL's activating switch in NED triggered by a select repertoire of IP metabolites.
Copyright © 2019 Elsevier Ltd. All rights reserved.
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8 MeSH Terms
Crystallographic and kinetic analyses of human IPMK reveal disordered domains modulate ATP binding and kinase activity.
Seacrist CD, Blind RD
(2018) Sci Rep 8: 16672
MeSH Terms: Adenosine Triphosphate, Crystallography, Humans, Inositol Phosphates, Kinetics, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Binding, Protein Structure, Secondary, Signal Transduction
Show Abstract · Added January 19, 2019
Inositol polyphosphate multikinase (IPMK) is a member of the IPK-superfamily of kinases, catalyzing phosphorylation of several soluble inositols and the signaling phospholipid PI(4,5)P (PIP). IPMK also has critical non-catalytic roles in p53, mTOR/Raptor, TRAF6 and AMPK signaling mediated partly by two disordered domains. Although IPMK non-catalytic functions are well established, it is less clear if the disordered domains are important for IPMK kinase activity or ATP binding. Here, kinetic and structural analyses of an engineered human IPMK lacking all disordered domains (ΔIPMK) are presented. Although the K for PIP is identical between ΔIPMK and wild type, ΔIPMK has a 1.8-fold increase in k for PIP, indicating the native IPMK disordered domains decrease IPMK activity in vitro. The 2.5 Å crystal structure of ΔIPMK is reported, confirming the conserved ATP-grasp fold. A comparison with other IPK-superfamily structures revealed a putative "ATP-clamp" in the disordered N-terminus, we predicted would stabilize ATP binding. Consistent with this observation, removal of the ATP clamp sequence increases the K for ATP 4.9-fold, indicating the N-terminus enhances ATP binding to IPMK. Together, these structural and kinetic studies suggest in addition to mediating protein-protein interactions, the disordered domains of IPMK impart modulatory capacity to IPMK kinase activity through multiple kinetic mechanisms.
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10 MeSH Terms
Poly(Thioketal Urethane) Autograft Extenders in an Intertransverse Process Model of Bone Formation.
McGough MAP, Shiels SM, Boller LA, Zienkiewicz KJ, Duvall CL, Wenke JC, Guelcher SA
(2019) Tissue Eng Part A 25: 949-963
MeSH Terms: Animals, Autografts, Bone Transplantation, Calcium Phosphates, Catalysis, Cell Line, Mice, Models, Biological, Osteogenesis, Polyurethanes, Rabbits, Rats, Nude, Sheep, X-Ray Microtomography
Show Abstract · Added April 10, 2019
IMPACT STATEMENT - The development of autograft extenders is a significant clinical need in bone tissue engineering. We report new settable poly(thioketal urethane)-based autograft extenders that have bone-like mechanical properties and handling properties comparable to calcium phosphate bone cements. These settable autograft extenders remodeled to form new bone in a biologically stringent intertransverse process model of bone formation that does not heal when treated with calcium phosphate bone void fillers or cements alone. This is the first study to report settable autograft extenders with bone-like strength and handling properties comparable to ceramic bone cements, which have the potential to improve treatment of bone fractures and other orthopedic conditions.
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14 MeSH Terms
Localized low-dose rhBMP-2 is effective at promoting bone regeneration in mandibular segmental defects.
Carlisle P, Guda T, Silliman DT, Burdette AJ, Talley AD, Alvarez R, Tucker D, Hale RG, Guelcher SA, BrownBaer PR
(2019) J Biomed Mater Res B Appl Biomater 107: 1491-1503
MeSH Terms: Animals, Bone Morphogenetic Protein 2, Bone Regeneration, Calcium Phosphates, Drug Delivery Systems, Durapatite, Humans, Mandible, Mandibular Injuries, Recombinant Proteins, Swine, Swine, Miniature, Tomography, X-Ray Computed
Show Abstract · Added March 20, 2020
At least 26% of recent battlefield injuries are to the craniomaxillofacial (CMF) region. Recombinant human bone morphogenetic protein 2 (rhBMP-2) is used to treat CMF open fractures, but several complications have been associated with its use. This study tested the efficacy and safety of a lower (30% recommended) dose of rhBMP-2 to treat mandibular fractures. rhBMP-2 delivered via a polyurethane (PUR) and hydroxyapatite/β-tricalcium phosphate (Mastergraft®) scaffold was evaluated in a 2 cm segmental mandibular defect in minipigs. Bone regeneration was analyzed at 4, 8, and 12 weeks postsurgery using clinical computed tomography (CT) and rhBMP-2, and inflammatory marker concentrations were analyzed in serum and surgery-site drain effluent. CT scans revealed that pigs treated with PUR-Mastergraft® + rhBMP-2 had complete bone bridging, while the negative control group showed incomplete bone-bridging (n = 6). Volumetric analysis of regenerated bone showed that the PUR-Mastergraft® + rhBMP-2 treatment generated significantly more bone than control by 4 weeks, a trend that continued through 12 weeks. Variations in inflammatory analytes were detected in drain effluent samples and saliva but not in serum, suggesting a localized healing response. Importantly, the rhBMP-2 group did not exhibit an excessive increase in inflammatory analytes compared to control. Treatment with low-dose rhBMP-2 increases bone regeneration capacity in pigs with mandibular continuity defects and restores bone quality. Negative complications from rhBMP-2, such as excessive inflammatory analyte levels, were not observed. Together, these results suggest that treatment with low-dose rhBMP-2 is efficacious and may improve safety when treating CMF open fractures. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater 107B: 1491-1503, 2019.
© 2018 Wiley Periodicals, Inc.
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13 MeSH Terms
Architecture-Guided Fluid Flow Directs Renal Biomineralization.
Ho SP, Chen L, Allen FI, Hsi RS, Shimotake AR, Wiener SV, Kang M, Minor AM, Stoller ML
(2018) Sci Rep 8: 14157
MeSH Terms: Biomineralization, Calcium Phosphates, Humans, Kidney Medulla, Minerals, Nephrocalcinosis, X-Ray Microtomography
Show Abstract · Added February 26, 2019
Nephrocalcinosis often begins on a calcium phosphate deposit, at the tip of the medullo-papillary complex (MPC) known as Randall's plaque (RP). Contextualizing proximally observed biominerals within the MPC has led us to postulate a mechanobiological switch that can trigger interstitial biomineralization at the MPC tip, remote from the intratubular biominerals. Micro X-ray computed tomography scans of human MPCs correlated with transmission and scanning electron micrographs, and X-ray energy dispersive spectrometry demonstrated novel findings about anatomically-specific biominerals. An abundance of proximal intratubular biominerals were associated with emergence of distal interstitial RP. The fundamental architecture of the MPC and mineral densities at the proximal and distal locations of the MPC differed markedly. A predominance of plate-like minerals or radially oriented plate-like crystallites within spheroidal minerals in the proximal intratubular locations, and core-shell type crystallites within spheroidal minerals in distal interstitial locations were observed. Based on the MPC anatomic location of structure-specific biominerals, a biological switch within the mineral-free zone occurring between the proximal and distal locations is postulated. The "on" and "off" switch is dependent on changes in the pressure differential resulting from changes in tubule diameters; the "Venturi effect" changes the "circumferential strain" and culminates in interstitial crystal deposits in the distal tubule wall in response to proximal tubular obstruction. These distal interstitial mineralizations can emerge into the collecting system of the kidney linking nephrocalcinosis with nephrolithiasis.
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7 MeSH Terms
Genetic Variants Associated with Circulating Fibroblast Growth Factor 23.
Robinson-Cohen C, Bartz TM, Lai D, Ikizler TA, Peacock M, Imel EA, Michos ED, Foroud TM, Akesson K, Taylor KD, Malmgren L, Matsushita K, Nethander M, Eriksson J, Ohlsson C, Mellström D, Wolf M, Ljunggren O, McGuigan F, Rotter JI, Karlsson M, Econs MJ, Ix JH, Lutsey PL, Psaty BM, de Boer IH, Kestenbaum BR
(2018) J Am Soc Nephrol 29: 2583-2592
MeSH Terms: African Continental Ancestry Group, Cohort Studies, European Continental Ancestry Group, Female, Fibroblast Growth Factors, Genome-Wide Association Study, Humans, Kidney, Male, Phosphates, Polymorphism, Single Nucleotide, RGS Proteins, Sodium-Phosphate Cotransporter Proteins, Type IIa, Vitamin D, Vitamin D3 24-Hydroxylase
Show Abstract · Added January 3, 2019
BACKGROUND - Fibroblast growth factor 23 (FGF23), a bone-derived hormone that regulates phosphorus and vitamin D metabolism, contributes to the pathogenesis of mineral and bone disorders in CKD and is an emerging cardiovascular risk factor. Central elements of FGF23 regulation remain incompletely understood; genetic variation may help explain interindividual differences.
METHODS - We performed a meta-analysis of genome-wide association studies of circulating FGF23 concentrations among 16,624 participants of European ancestry from seven cohort studies, excluding participants with eGFR<30 ml/min per 1.73 m to focus on FGF23 under normal conditions. We evaluated the association of single-nucleotide polymorphisms (SNPs) with natural log-transformed FGF23 concentration, adjusted for age, sex, study site, and principal components of ancestry. A second model additionally adjusted for BMI and eGFR.
RESULTS - We discovered 154 SNPs from five independent regions associated with FGF23 concentration. The SNP with the strongest association, rs17216707 (=3.0×10), lies upstream of , which encodes the primary catabolic enzyme for 1,25-dihydroxyvitamin D and 25-hydroxyvitamin D. Each additional copy of the T allele at this locus is associated with 5% higher FGF23 concentration. Another locus strongly associated with variations in FGF23 concentration is rs11741640, within and upstream of (a gene involved in renal phosphate transport). Additional adjustment for BMI and eGFR did not materially alter the magnitude of these associations. Another top locus (within , the ABO blood group transferase gene) was no longer statistically significant at the genome-wide level.
CONCLUSIONS - Common genetic variants located near genes involved in vitamin D metabolism and renal phosphate transport are associated with differences in circulating FGF23 concentrations.
Copyright © 2018 by the American Society of Nephrology.
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15 MeSH Terms
MLKL Requires the Inositol Phosphate Code to Execute Necroptosis.
Dovey CM, Diep J, Clarke BP, Hale AT, McNamara DE, Guo H, Brown NW, Cao JY, Grace CR, Gough PJ, Bertin J, Dixon SJ, Fiedler D, Mocarski ES, Kaiser WJ, Moldoveanu T, York JD, Carette JE
(2018) Mol Cell 70: 936-948.e7
MeSH Terms: Binding Sites, Cell Death, Colonic Neoplasms, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, HT29 Cells, Herpesvirus 1, Human, Humans, Inositol Phosphates, Jurkat Cells, Mutation, Phosphorylation, Phosphotransferases (Alcohol Group Acceptor), Protein Kinases, Receptor-Interacting Protein Serine-Threonine Kinases, Signal Transduction, Tumor Necrosis Factor-alpha
Show Abstract · Added March 30, 2020
Necroptosis is an important form of lytic cell death triggered by injury and infection, but whether mixed lineage kinase domain-like (MLKL) is sufficient to execute this pathway is unknown. In a genetic selection for human cell mutants defective for MLKL-dependent necroptosis, we identified mutations in IPMK and ITPK1, which encode inositol phosphate (IP) kinases that regulate the IP code of soluble molecules. We show that IP kinases are essential for necroptosis triggered by death receptor activation, herpesvirus infection, or a pro-necrotic MLKL mutant. In IP kinase mutant cells, MLKL failed to oligomerize and localize to membranes despite proper receptor-interacting protein kinase-3 (RIPK3)-dependent phosphorylation. We demonstrate that necroptosis requires IP-specific kinase activity and that a highly phosphorylated product, but not a lowly phosphorylated precursor, potently displaces the MLKL auto-inhibitory brace region. These observations reveal control of MLKL-mediated necroptosis by a metabolite and identify a key molecular mechanism underlying regulated cell death.
Copyright © 2018 Elsevier Inc. All rights reserved.
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MeSH Terms
Structural basis of ligand binding modes at the neuropeptide Y Y receptor.
Yang Z, Han S, Keller M, Kaiser A, Bender BJ, Bosse M, Burkert K, Kögler LM, Wifling D, Bernhardt G, Plank N, Littmann T, Schmidt P, Yi C, Li B, Ye S, Zhang R, Xu B, Larhammar D, Stevens RC, Huster D, Meiler J, Zhao Q, Beck-Sickinger AG, Buschauer A, Wu B
(2018) Nature 556: 520-524
MeSH Terms: Arginine, Binding Sites, Crystallography, X-Ray, Dihydropyridines, Diphenylacetic Acids, Humans, Inositol Phosphates, Ligands, Molecular Docking Simulation, Mutant Proteins, Mutation, Neuropeptide Y, Nuclear Magnetic Resonance, Biomolecular, Phenylurea Compounds, Protein Binding, Receptors, Neuropeptide Y, Structure-Activity Relationship, Substrate Specificity
Show Abstract · Added March 21, 2020
Neuropeptide Y (NPY) receptors belong to the G-protein-coupled receptor superfamily and have important roles in food intake, anxiety and cancer biology . The NPY-Y receptor system has emerged as one of the most complex networks with three peptide ligands (NPY, peptide YY and pancreatic polypeptide) binding to four receptors in most mammals, namely the Y, Y, Y and Y receptors, with different affinity and selectivity . NPY is the most powerful stimulant of food intake and this effect is primarily mediated by the Y receptor (YR) . A number of peptides and small-molecule compounds have been characterized as YR antagonists and have shown clinical potential in the treatment of obesity , tumour and bone loss . However, their clinical usage has been hampered by low potency and selectivity, poor brain penetration ability or lack of oral bioavailability . Here we report crystal structures of the human YR bound to the two selective antagonists UR-MK299 and BMS-193885 at 2.7 and 3.0 Å resolution, respectively. The structures combined with mutagenesis studies reveal the binding modes of YR to several structurally diverse antagonists and the determinants of ligand selectivity. The YR structure and molecular docking of the endogenous agonist NPY, together with nuclear magnetic resonance, photo-crosslinking and functional studies, provide insights into the binding behaviour of the agonist and for the first time, to our knowledge, determine the interaction of its N terminus with the receptor. These insights into YR can enable structure-based drug discovery that targets NPY receptors.
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MeSH Terms
The Par3 polarity protein is an exocyst receptor essential for mammary cell survival.
Ahmed SM, Macara IG
(2017) Nat Commun 8: 14867
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Apoptosis, Cadherins, Cell Adhesion Molecules, Cell Cycle Proteins, Cell Line, Cell Polarity, Cell Survival, Enzyme Activation, Epithelial Cells, Female, Gene Knockdown Techniques, Golgi Apparatus, Humans, Lysine, Mammary Glands, Animal, Models, Biological, PTEN Phosphohydrolase, Phosphatidylinositol Phosphates, Phosphorylation, Protein Domains, Proto-Oncogene Proteins c-akt, Vesicular Transport Proteins, rab GTP-Binding Proteins
Show Abstract · Added April 26, 2017
The exocyst is an essential component of the secretory pathway required for delivery of basolateral proteins to the plasma membranes of epithelial cells. Delivery occurs adjacent to tight junctions (TJ), suggesting that it recognizes a receptor at this location. However, no such receptor has been identified. The Par3 polarity protein associates with TJs but has no known function in membrane traffic. We now show that, unexpectedly, Par3 is essential for mammary cell survival. Par3 silencing causes apoptosis, triggered by phosphoinositide trisphosphate depletion and decreased Akt phosphorylation, resulting from failure of the exocyst to deliver basolateral proteins to the cortex. A small region of PAR3 binds directly to Exo70 and is sufficient for exocyst docking, membrane-protein delivery and cell survival. PAR3 lacking this domain can associate with the cortex but cannot support exocyst function. We conclude that Par3 is the long-sought exocyst receptor required for targeted membrane-protein delivery.
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25 MeSH Terms
A comparative assessment of preclinical chemotherapeutic response of tumors using quantitative non-Gaussian diffusion MRI.
Xu J, Li K, Smith RA, Waterton JC, Zhao P, Ding Z, Does MD, Manning HC, Gore JC
(2017) Magn Reson Imaging 37: 195-202
MeSH Terms: Animals, Bayes Theorem, Colonic Neoplasms, Diffusion Magnetic Resonance Imaging, Dimethyl Sulfoxide, Disease Models, Animal, Female, Humans, Mice, Mice, Nude, Models, Statistical, Organophosphates, Protein Kinase Inhibitors, Quinazolines
Show Abstract · Added April 6, 2017
BACKGROUND - Diffusion-weighted MRI (DWI) signal attenuation is often not mono-exponential (i.e. non-Gaussian diffusion) with stronger diffusion weighting. Several non-Gaussian diffusion models have been developed and may provide new information or higher sensitivity compared with the conventional apparent diffusion coefficient (ADC) method. However the relative merits of these models to detect tumor therapeutic response is not fully clear.
METHODS - Conventional ADC, and three widely-used non-Gaussian models, (bi-exponential, stretched exponential, and statistical model), were implemented and compared for assessing SW620 human colon cancer xenografts responding to barasertib, an agent known to induce apoptosis via polyploidy. Bayesian Information Criterion (BIC) was used for model selection among all three non-Gaussian models.
RESULTS - All of tumor volume, histology, conventional ADC, and three non-Gaussian DWI models could show significant differences between control and treatment groups after four days of treatment. However, only the non-Gaussian models detected significant changes after two days of treatment. For any treatment or control group, over 65.7% of tumor voxels indicate the bi-exponential model is strongly or very strongly preferred.
CONCLUSION - Non-Gaussian DWI model-derived biomarkers are capable of detecting tumor earlier chemotherapeutic response of tumors compared with conventional ADC and tumor volume. The bi-exponential model provides better fitting compared with statistical and stretched exponential models for the tumor and treatment models used in the current work.
Copyright © 2016 Elsevier Inc. All rights reserved.
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14 MeSH Terms