Glycans are critically involved in a variety of physiological and pathological process, such as cell differentiation, host-pathogen interactions, and inflammation. This abundant class of biomolecules is found both inside and outside the cell where they meditate signaling cascades or modify the stability and function of other macromolecules such as proteins or lipids. Despite their abundance and biological importance, our understanding of structure-function relationships among glycans remains understudied and presents exciting opportunities for new discoveries.
In the Hsieh-Wilson lab, we combine chemical synthesis, biochemical assays, and cellular and in vivo studies to investigate the molecular functions of glycans and characterize their structure-function relationships.
In the Hsieh-Wilson lab, we combine chemical synthesis, biochemical assays, and cellular and in vivo studies to investigate the molecular functions of glycans and characterize their structure-function relationships.
Decoding heparan sulfate structure and function
Heparan sulfate (HS) and heparin are polysaccharides that undergo extensive post-glycosylational modification, giving rise to an immense diversity of sulfated structures. This diversity imbues HS with the ability to bind a wide array of protein partners, thus mediating many processes such as cell differentiation, pathogen invasion and infection, and blood coagulation. However, the molecular recognition of HS and HS-binding proteins remains largely uncharacterized. To decode HS structure-function relationships, we have developed automated synthetic methods to improve access across HS structure space, generated a suite of cell surface remodeling tools and glycomimetic polymers, and are developing small molecule inhibitors to interrogate HS activity in vivo. Find out more...
Keywords: carbohydrate chemistry, synthetic methods, molecular recognition, microarrays, biomimetics, directed evolution, biophysical methods, structural biology, molecular modeling
Heparan sulfate (HS) and heparin are polysaccharides that undergo extensive post-glycosylational modification, giving rise to an immense diversity of sulfated structures. This diversity imbues HS with the ability to bind a wide array of protein partners, thus mediating many processes such as cell differentiation, pathogen invasion and infection, and blood coagulation. However, the molecular recognition of HS and HS-binding proteins remains largely uncharacterized. To decode HS structure-function relationships, we have developed automated synthetic methods to improve access across HS structure space, generated a suite of cell surface remodeling tools and glycomimetic polymers, and are developing small molecule inhibitors to interrogate HS activity in vivo. Find out more...
Keywords: carbohydrate chemistry, synthetic methods, molecular recognition, microarrays, biomimetics, directed evolution, biophysical methods, structural biology, molecular modeling
Neuroplasticity and chondroitin sulfate
Chondroitin sulfate proteoglycans (CSPGs) are a key component of the extracellular matrix in the central nervous system, where they are essential to many important processes in development, neuroplasticity, memory, and neurodegeneration. Found covalently anchored to a core protein, chondroitin sulfate (CS) chains are decorated with sulfate groups that give rise to unique combinations of sulfation motifs. These motifs serve as recognition elements for protein ligands and mediate the aforementioned biological processes. To characterize the structure-function relationships of CS and CSPGs, we utilize synthetic methods to access defined structures, have developed antibodies that enable selective targeting of motifs for cellular and in vivo functional studies, and identified the first class of cell-permeable CS sulfotransferase inhibitors. Using a combination of these chemical and biological tools, we examine how CS sulfation regulates neural physiology and disease. Find out more...
Keywords: CNS disease, neuroregeneration, immunology, viral vectors, medicinal chemistry, enzyme inhibition, cellular assays, chemical probes
Chondroitin sulfate proteoglycans (CSPGs) are a key component of the extracellular matrix in the central nervous system, where they are essential to many important processes in development, neuroplasticity, memory, and neurodegeneration. Found covalently anchored to a core protein, chondroitin sulfate (CS) chains are decorated with sulfate groups that give rise to unique combinations of sulfation motifs. These motifs serve as recognition elements for protein ligands and mediate the aforementioned biological processes. To characterize the structure-function relationships of CS and CSPGs, we utilize synthetic methods to access defined structures, have developed antibodies that enable selective targeting of motifs for cellular and in vivo functional studies, and identified the first class of cell-permeable CS sulfotransferase inhibitors. Using a combination of these chemical and biological tools, we examine how CS sulfation regulates neural physiology and disease. Find out more...
Keywords: CNS disease, neuroregeneration, immunology, viral vectors, medicinal chemistry, enzyme inhibition, cellular assays, chemical probes
O-GlcNAc and other dynamic protein modifications
O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification on intracellular serine and threonine residues. A ubiquitous and abundant modification, O-GlcNAcylation regulates processes including transcription, translation, metabolic flux, and signaling. Consequently, this modification is linked to diseases such as diabetes, cancer and Alzheimer’s disease. Our lab has developed highly specific methods of labeling O-GlcNAc, which have contributed significantly to the identification of the O-GlcNAcylated proteome. Recently, we have expanded our proteomics methods to encompass the identification of proteins that interact with O-GlcNAc cycling enzymes OGT and OGA. Through in vitro and cellular assays, we characterizethe roles that individual O-GlcNAc modifications have in cellular function and disease. Find out more...
Keywords: PTM interplay, proteomics, protein structure and function, enzyme regulation, neurodegenerative disease, chemoenzymatic labeling, bioorthogonal chemistry
O-linked N-acetylglucosamine (O-GlcNAc) is a dynamic post-translational modification on intracellular serine and threonine residues. A ubiquitous and abundant modification, O-GlcNAcylation regulates processes including transcription, translation, metabolic flux, and signaling. Consequently, this modification is linked to diseases such as diabetes, cancer and Alzheimer’s disease. Our lab has developed highly specific methods of labeling O-GlcNAc, which have contributed significantly to the identification of the O-GlcNAcylated proteome. Recently, we have expanded our proteomics methods to encompass the identification of proteins that interact with O-GlcNAc cycling enzymes OGT and OGA. Through in vitro and cellular assays, we characterizethe roles that individual O-GlcNAc modifications have in cellular function and disease. Find out more...
Keywords: PTM interplay, proteomics, protein structure and function, enzyme regulation, neurodegenerative disease, chemoenzymatic labeling, bioorthogonal chemistry
Glycan structure identification at the single-cell level
Over the years, our lab has developed chemical tools to identify intracellular and cell surface glycans, their corresponding glycoproteins, and their binding partners. Used together, these tools provide insights into glycan-mediated signaling effects and downstream cellular responses. Discerning cell signaling interactions in individual cell types represents an important advancement for study of heterogeneous and complex tissues such as the brain. Our lab has developed a method to simultaneously profile glycan and gene expression at the level of single cells, which allows the synchronous identification of glycans, glycoproteins, and binding partners, and provides a new, high-resolution framework for identification of signaling interactions. Broadly, these methods enable the study of the roles of glycans in development, memory formation, learning, and neurodegenerative diseases. Find out more...
Keywords: chemoenzymatic and metabolic labeling, cell surface engineering, single-cell technology, bioinformatics, systems biology
Over the years, our lab has developed chemical tools to identify intracellular and cell surface glycans, their corresponding glycoproteins, and their binding partners. Used together, these tools provide insights into glycan-mediated signaling effects and downstream cellular responses. Discerning cell signaling interactions in individual cell types represents an important advancement for study of heterogeneous and complex tissues such as the brain. Our lab has developed a method to simultaneously profile glycan and gene expression at the level of single cells, which allows the synchronous identification of glycans, glycoproteins, and binding partners, and provides a new, high-resolution framework for identification of signaling interactions. Broadly, these methods enable the study of the roles of glycans in development, memory formation, learning, and neurodegenerative diseases. Find out more...
Keywords: chemoenzymatic and metabolic labeling, cell surface engineering, single-cell technology, bioinformatics, systems biology
