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26. Heparin-mediated dimerization of follistatin

Author

Walker, Ryan G, Kattamuri, Chandramohan, Goebel, Erich J, Zhang, Fuming, Hammel, Michal, Tainer, John A, Linhardt, Robert J, and Thompson, Thomas B

Subjects
Biochemistry and Cell Biology, Biological Sciences, Activins, Animals, CHO Cells, Cricetulus, Follistatin, Heparin, Humans, Inhibitory Concentration 50, Ligands, Models, Molecular, Myostatin, Protein Multimerization, Scattering, Small Angle, Static Electricity, Swine, X-Ray Diffraction, activin, myostatin, heparin, heparan sulfate, transforming growth factor beta, Medical and Health Sciences, Biochemistry & Molecular Biology, Biological sciences, Biomedical and clinical sciences, Engineering
Abstract

Heparin and heparan sulfate (HS) are highly sulfated polysaccharides covalently bound to cell surface proteins, which directly interact with many extracellular proteins, including the transforming growth factor-β (TGFβ) family ligand antagonist, follistatin 288 (FS288). Follistatin neutralizes the TGFβ ligands, myostatin and activin A, by forming a nearly irreversible non-signaling complex by surrounding the ligand and preventing interaction with TGFβ receptors. The FS288-ligand complex has higher affinity than unbound FS288 for heparin/HS, which accelerates ligand internalization and lysosomal degradation; however, limited information is available for how FS288 interactions with heparin affect ligand binding. Using surface plasmon resonance (SPR) we show that preincubation of FS288 with heparin/HS significantly decreased the association kinetics for both myostatin and activin A with seemingly no effect on the dissociation rate. This observation is dependent on the heparin/HS chain length where small chain lengths less than degree of polymerization 10 (dp10) did not alter association rates but chain lengths >dp10 decreased association rates. In an attempt to understand the mechanism for this observation, we uncovered that heparin induced dimerization of follistatin. Consistent with our SPR results, we found that dimerization only occurs with heparin molecules >dp10. Small-angle X-ray scattering of the FS288 heparin complex supports that FS288 adopts a dimeric configuration that is similar to the FS288 dimer in the ligand-bound state. These results indicate that heparin mediates dimerization of FS288 in a chain-length-dependent manner that reduces the ligand association rate, but not the dissociation rate or antagonistic activity of FS288.

Published
2021

32. FAM20B-catalyzed glycosaminoglycans control murine tooth number by restricting FGFR2b signaling

Author

Wu, Jingyi, Tian, Ye, Han, Lu, Liu, Chao, Sun, Tianyu, Li, Ling, Yu, Yanlei, Lamichhane, Bikash, D’Souza, Rena N, Millar, Sarah E, Krumlauf, Robb, Ornitz, David M, Feng, Jian Q, Klein, Ophir, Zhao, Hu, Zhang, Fuming, Linhardt, Robert J, and Wang, Xiaofang

Subjects
Biochemistry and Cell Biology, Biological Sciences, Dental/Oral and Craniofacial Disease, Stem Cell Research - Nonembryonic - Non-Human, Regenerative Medicine, Stem Cell Research, 1.1 Normal biological development and functioning, Underpinning research, Oral and gastrointestinal, Animals, Cell Differentiation, Glycosaminoglycans, Mice, Odontogenesis, Phosphotransferases (Alcohol Group Acceptor), Receptor, Fibroblast Growth Factor, Type 2, Signal Transduction, Stem Cells, Tooth, Supernumerary, Glycosaminoglycan, Proteoglycan, Fam20B, Kinase, Supernumerary teeth, Tooth renewal, Tooth replacement, Extracellular matrix, Stem cell, Sox2, Developmental Biology, Biological sciences
Abstract

BackgroundThe formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood.ResultsIn this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial GAGs confine murine tooth number by restricting the homeostasis of Sox2(+) dental epithelial stem/progenitor cells in a non-autonomous manner. FAM20B-catalyzed GAGs regulate the cell fate of dental lamina by restricting FGFR2b signaling at the initial stage of tooth development to maintain a subtle balance between the renewal and differentiation of Sox2(+) cells. At the later cap stage, WNT signaling functions as a relay cue to facilitate the supernumerary tooth formation.ConclusionsThe novel mechanism we have characterized through which GAGs control the tooth number in mice may also be more broadly relevant for potentiating signaling interactions in other tissues during development and tissue homeostasis.

Published
2020

42. Major Differences between the Self-Assembly and Seeding Behavior of Heparin-Induced and in Vitro Phosphorylated Tau and Their Modulation by Potential Inhibitors

Author

Despres, Clément, Di, Jing, Cantrelle, François-Xavier, Li, Zizheng, Huvent, Isabelle, Chambraud, Béatrice, Zhao, Jing, Chen, Jianle, Chen, Shiguo, Lippens, Guy, Zhang, Fuming, Linhardt, Robert, Wang, Chunyu, Klärner, Frank-Gerrit, Schrader, Thomas, Landrieu, Isabelle, Bitan, Gal, and Smet-Nocca, Caroline

Subjects
Biochemistry and Cell Biology, Biological Sciences, Brain Disorders, Alzheimer's Disease, Acquired Cognitive Impairment, Neurodegenerative, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Neurosciences, Dementia, Aging, Aetiology, 2.1 Biological and endogenous factors, Neurological, Alzheimer Disease, Animals, Heparin, Humans, Phosphorylation, Rats, tau Proteins, Chemical Sciences, Organic Chemistry, Biological sciences, Chemical sciences
Abstract

Self-assembly of the microtubule-associated protein tau into neurotoxic oligomers, fibrils, and paired helical filaments, and cell-to-cell spreading of these pathological tau species are critical processes underlying the pathogenesis of Alzheimer's disease and other tauopathies. Modulating the self-assembly process and inhibiting formation and spreading of such toxic species are promising strategies for therapy development. A challenge in investigating tau self-assembly in vitro is that, unlike most amyloidogenic proteins, tau does not aggregate in the absence of posttranslational modifications (PTM), aggregation inducers, or preformed seeds. The most common induction method is addition of polyanions, such as heparin; yet, this artificial system may not represent adequately tau self-assembly in vivo, which is driven by aberrant phosphorylation and other PTMs, potentially leading to in vitro data that do not reflect the behavior of tau and its interaction with modulators in vivo. To tackle these challenges, methods for in vitro phosphorylation of tau to produce aggregation-competent forms recently have been introduced ( Despres et al. ( 2017 ) Proc. Natl. Acad. Sci. U.S.A. , 114 , 9080 - 9085 ). However, the oligomerization, seeding, and interaction with assembly modulators of the different forms of tau have not been studied to date. To address these knowledge gaps, we compared here side-by-side the self-assembly and seeding activity of heparin-induced tau with two forms of in vitro phosphorylated tau and tested how the molecular tweezer CLR01, a negatively charged compound, affected these processes. Tau was phosphorylated by incubation either with activated extracellular signal-regulated kinase 2 or with a whole rat brain extract. Seeding activity was measured using a fluorescence-resonance energy transfer-based biosensor-cell method. We also used solution-state NMR to investigate the binding sites of CLR01 on tau and how they were impacted by phosphorylation. Our systematic structure-activity relationship study demonstrates that heparin-induced tau behaves differently from in vitro phosphorylated tau. The aggregation rates of the different forms are distinct as is the intracellular localization of the induced aggregates, which resemble brain-derived tau strains suggesting that heparin-induced tau and in vitro phosphorylated tau have different conformations, properties, and activities. CLR01 inhibits aggregation and seeding of both heparin-induced and in vitro phosphorylated tau dose-dependently, although heparin induction interferes with the interaction between CLR01 and tau.

Published
2019

43. Heavy Heparin: A Stable Isotope‐Enriched, Chemoenzymatically‐Synthesized, Poly‐Component Drug

Author

Cress, Brady F, Bhaskar, Ujjwal, Vaidyanathan, Deepika, Williams, Asher, Cai, Chao, Liu, Xinyue, Fu, Li, M‐Chari, Vandhana, Zhang, Fuming, Mousa, Shaker A, Dordick, Jonathan S, Koffas, Mattheos AG, and Linhardt, Robert J

Subjects
Medicinal and Biomolecular Chemistry, Chemical Sciences, Rare Diseases, Orphan Drug, Animals, Anticoagulants, Heparin, Humans, Rabbits, chemoenzymatic synthesis, deuterated drugs, heparin, pharmacology, stable isotope labeling, Organic Chemistry, Chemical sciences
Abstract

Heparin is a highly sulfated, complex polysaccharide and widely used anticoagulant pharmaceutical. In this work, we chemoenzymatically synthesized perdeuteroheparin from biosynthetically enriched heparosan precursor obtained from microbial culture in deuterated medium. Chemical de-N-acetylation, chemical N-sulfation, enzymatic epimerization, and enzymatic sulfation with recombinant heparin biosynthetic enzymes afforded perdeuteroheparin comparable to pharmaceutical heparin. A series of applications for heavy heparin and its heavy biosynthetic intermediates are demonstrated, including generation of stable isotope labeled disaccharide standards, development of a non-radioactive NMR assay for glucuronosyl-C5-epimerase, and background-free quantification of in vivo half-life following administration to rabbits. We anticipate that this approach can be extended to produce other isotope-enriched glycosaminoglycans.

Published
2019

49. Soluble α-klotho and heparin modulate the pathologic cardiac actions of fibroblast growth factor 23 in chronic kidney disease

Author

Yanucil, Christopher, Kentrup, Dominik, Campos, Isaac, Czaya, Brian, Heitman, Kylie, Westbrook, David, Osis, Gunars, Grabner, Alexander, Wende, Adam R., Vallejo, Julian, Wacker, Michael J., Navarro-Garcia, Jose Alberto, Ruiz-Hurtado, Gema, Zhang, Fuming, Song, Yuefan, Linhardt, Robert J., White, Kenneth, Kapiloff, Michael S., and Faul, Christian

Published
2022
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