Linda Hsieh-Wilson

Last updated
Linda Carol Hsieh-Wilson
Alma mater University of California, Berkeley
Scientific career
FieldsChemical neurobiology
Institutions California Institute of Technology
Doctoral advisor Peter G. Schultz

Linda Carol Hsieh-Wilson is an American chemist and the Milton and Rosalind Chang Professor of Chemistry at the California Institute of Technology. She is known for her work in chemical neurobiology on understanding the structure and function of carbohydrates in the nervous system. Her studies have revealed critical roles for carbohydrates and protein glycosylation in fundamental processes ranging from cellular metabolism to memory storage. She is a member of the American Academy of Arts and Sciences and was elected to the National Academy of Sciences in 2022.

Contents

Biography

Hsieh-Wilson was born in New York City, NY and received her bachelor's degree in chemistry at Yale University, where she graduated magna cum laude. She then completed her Ph.D. in 1996 at the University of California, Berkeley, where she was a National Science Foundation Fellow in the laboratory of Peter G. Schultz and studied antibody-based catalysis. [1] [2] She then joined the lab of Professor and Nobel Prize Laureate Paul Greengard at Rockefeller University, where she characterized the protein phosphatase and actin-binding protein spinophilin [3] and investigated its role in dendritic spines. [4] [5] Hsieh-Wilson obtained an appointment in the Division of Chemistry and Chemical Engineering at the California Institute of Technology in 2000 as an assistant professor and became an investigator at the Howard Hughes Medical Institute in 2005. She was appointed to associate professor of chemistry in 2006 and full professor of chemistry at the California Institute of Technology in 2010. [6]

Research interests

Overview

Hsieh-Wilson's research is at the interface between organic chemistry and neuroscience. [7] She investigates how the post-translational addition of glycans affect the structure and function of proteins in the nervous system. Her laboratory has developed a chemoenzymatic method to tag proteins that have been appended with a dynamic form of glycosylation called O-GlcNAc. [8] Her work with glycosaminoglycan microarrays has significantly advanced an understanding of specific sulfated glycosaminoglycans in neuronal communication, learning, and memory as well as advanced the field of chemical biology. [9] She has demonstrated how fucosylation can modulate neurite growth and neuronal morphology. [10]

O-GlcNAc Glycosylation

Hsieh-Wilson and her colleagues have found that the covalent-modifications of intercellular proteins by O-linked-N-acetylglucosamine (O-GlcNAc) within the mammalian nervous system have a large role in the regulation of gene expression, neuronal signaling, and synaptic plasticity. [11] This post-translational modification, has been analysed in the rat brain using a novel chemoenzymatic strategy wherein O-GlcNAc modified proteins are selectively labeled with fluorescent or biotin tags. This technique developed by Hsieh-Wilson and her lab has revealed over 200 O-GlcNAc modified proteins within the mammalian brain and such modifications have been shown to activate transcriptional function of proteins, [12] regulate cancer metabolism, [13] regulate gene expression and memory formation, [14] and carry out many other tasks in the brain and beyond.

Glycosaminoglycans

Glycosaminoglycans are heterogeneously sulfated oligosaccharides that are very important in nervous system development, spinal cord injury, inflammation and cancer metastasis. Hsieh-Wilson's research on this subject implicates the specific sulfation sequence of glycosaminoglycans as a way to modulate biological function. Specifically, her work with chondroitin sulfate (CS) and heparan sulfate (HS), the two most common glycosaminoglycans in the nervous system, has shown that this "sulfation code" functions as a molecular recognition element for growth factors and modulates neuronal growth, [15] [16] indicating that these specific sulfated glycosaminoglycans play a major role in neuronal communication, learning, and memory. Additionally, Hsieh-Wilson has elucidated the role of this sulfation in glycosaminoglycan-protein interaction using a carbohydrate microarray-based approach developed in her lab. [17]

Notable papers

The Web of Science lists 51 publications in peer-reviewed scientific journals that have been cited over 1200 times, leading to an h-index of 21. [18] Her three most cited papers (>90 times) are: [18]

  1. Yan Z, Hsieh-Wilson L, Feng J, Tomizawa K, Allen PB, Fienberg AA, Nairn AC, Greengard P (January 1999). "Protein phosphatase 1 modulation of neostriatal AMPA channels: regulation by DARPP-32 and spinophilin". Nature Neuroscience . 2 (1): 13–7. doi:10.1038/4516. PMID   10195174. S2CID   2534174.
  2. Khidekel N, Ficarro SB, Peters EC, Hsieh-Wilson LC (September 2004). "Exploring the O-GlcNAc proteome: direct identification of O-GlcNAc-modified proteins from the brain". Proceedings of the National Academy of Sciences of the United States of America . 101 (36): 13132–7. Bibcode:2004PNAS..10113132K. doi: 10.1073/pnas.0403471101 . PMC   516536 . PMID   15340146.
  3. Gama CI, Tully SE, Sotogaku N, Clark PM, Rawat M, Vaidehi N, Goddard WA, Nishi A, Hsieh-Wilson LC (September 2006). "Sulfation patterns of glycosaminoglycans encode molecular recognition and activity" (PDF). Nature Chemical Biology . 2 (9): 467–73. doi:10.1038/nchembio810. PMID   16878128. S2CID   1229340.

Awards and honors

Related Research Articles

A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the primary effectors of dephosphorylation and can be grouped into three main classes based on sequence, structure and catalytic function. The largest class of PPs is the phosphoprotein phosphatase (PPP) family comprising PP1, PP2A, PP2B, PP4, PP5, PP6 and PP7, and the protein phosphatase Mg2+- or Mn2+-dependent (PPM) family, composed primarily of PP2C. The protein Tyr phosphatase (PTP) super-family forms the second group, and the aspartate-based protein phosphatases the third. The protein pseudophosphatases form part of the larger phosphatase family, and in most cases are thought to be catalytically inert, instead functioning as phosphate-binding proteins, integrators of signalling or subcellular traps. Examples of membrane-spanning protein phosphatases containing both active (phosphatase) and inactive (pseudophosphatase) domains linked in tandem are known, conceptually similar to the kinase and pseudokinase domain polypeptide structure of the JAK pseudokinases. A complete comparative analysis of human phosphatases and pseudophosphatases has been completed by Manning and colleagues, forming a companion piece to the ground-breaking analysis of the human kinome, which encodes the complete set of ~536 human protein kinases.

<span class="mw-page-title-main">Glycoprotein</span> Protein with oligosaccharide modifications

Glycoproteins are proteins which contain oligosaccharide chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known as glycosylation. Secreted extracellular proteins are often glycosylated.

<span class="mw-page-title-main">Heparin</span> Anticoagulant

Heparin, also known as unfractionated heparin (UFH), is a medication and naturally occurring glycosaminoglycan. Since heparins depend on the activity of antithrombin, they are considered anticoagulants. Specifically it is also used in the treatment of heart attacks and unstable angina. It is given intravenously or by injection under the skin. Other uses for its anticoagulant properties include inside blood specimen test tubes and kidney dialysis machines.

<span class="mw-page-title-main">Glycosaminoglycan</span> Polysaccharides found in animal tissue

Glycosaminoglycans (GAGs) or mucopolysaccharides are long, linear polysaccharides consisting of repeating disaccharide units. The repeating two-sugar unit consists of a uronic sugar and an amino sugar, except in the case of the sulfated glycosaminoglycan keratan, where, in place of the uronic sugar there is a galactose unit. GAGs are found in vertebrates, invertebrates and bacteria. Because GAGs are highly polar molecules and attract water; the body uses them as lubricants or shock absorbers.

<span class="mw-page-title-main">Fondaparinux</span> Chemical compound

Fondaparinux is an anticoagulant medication chemically related to low molecular weight heparins. It is marketed by Viatris. A generic version developed by Alchemia is marketed within the US by Dr. Reddy's Laboratories.

<i>N</i>-Acetylglucosamine Biological molecule

N-Acetylglucosamine (GlcNAc) is an amide derivative of the monosaccharide glucose. It is a secondary amide between glucosamine and acetic acid. It is significant in several biological systems.

<span class="mw-page-title-main">Keratan sulfate</span> Class of chemical compounds

Keratan sulfate (KS), also called keratosulfate, is any of several sulfated glycosaminoglycans that have been found especially in the cornea, cartilage, and bone. It is also synthesized in the central nervous system where it participates both in development and in the glial scar formation following an injury. Keratan sulfates are large, highly hydrated molecules which in joints can act as a cushion to absorb mechanical shock.

<span class="mw-page-title-main">Heparan sulfate</span> Macromolecule

Heparan sulfate (HS) is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins. In this form, HS binds to a variety of protein ligands, including Wnt, and regulates a wide range of biological activities, including developmental processes, angiogenesis, blood coagulation, abolishing detachment activity by GrB, and tumour metastasis. HS has also been shown to serve as cellular receptor for a number of viruses, including the respiratory syncytial virus. One study suggests that cellular heparan sulfate has a role in SARS-CoV-2 Infection, particularly when the virus attaches with ACE2.

Uridine diphosphate <i>N</i>-acetylglucosamine Chemical compound

Uridine diphosphate N-acetylglucosamine or UDP-GlcNAc is a nucleotide sugar and a coenzyme in metabolism. It is used by glycosyltransferases to transfer N-acetylglucosamine residues to substrates. D-Glucosamine is made naturally in the form of glucosamine-6-phosphate, and is the biochemical precursor of all nitrogen-containing sugars. To be specific, glucosamine-6-phosphate is synthesized from fructose 6-phosphate and glutamine as the first step of the hexosamine biosynthesis pathway. The end-product of this pathway is UDP-GlcNAc, which is then used for making glycosaminoglycans, proteoglycans, and glycolipids.

<span class="mw-page-title-main">Pancreatic polypeptide receptor 1</span> Protein-coding gene in the species Homo sapiens

Pancreatic polypeptide receptor 1, also known as Neuropeptide Y receptor type 4, is a protein that in humans is encoded by the PPYR1 gene.

<span class="mw-page-title-main">PPP1R1B</span> Protein

Protein phosphatase 1 regulatory subunit 1B (PPP1R1B), also known as dopamine- and cAMP-regulated neuronal phosphoprotein (DARPP-32), is a protein that in humans is encoded by the PPP1R1B gene.

<span class="mw-page-title-main">PPP1R9B</span> Protein found in humans

Neurabin-2 is a protein that in humans is encoded by the PPP1R9B gene.

<span class="mw-page-title-main">B4GALT7</span> Protein-coding gene in the species Homo sapiens

Beta-1,4-galactosyltransferase 7 also known as galactosyltransferase I is an enzyme that in humans is encoded by the B4GALT7 gene. Galactosyltransferase I catalyzes the synthesis of the glycosaminoglycan-protein linkage in proteoglycans. Proteoglycans in turn are structural components of the extracellular matrix that is found between cells in connective tissues.

<span class="mw-page-title-main">CHST5</span> Protein-coding gene in the species Homo sapiens

Carbohydrate sulfotransferase 5 is an enzyme that in humans is encoded by the CHST5 gene.

Glycopeptides are peptides that contain carbohydrate moieties (glycans) covalently attached to the side chains of the amino acid residues that constitute the peptide.

<span class="mw-page-title-main">Synapsin I</span> Protein-coding gene in the species Homo sapiens

Synapsin I, is the collective name for Synapsin Ia and Synapsin Ib, two nearly identical phosphoproteins that in humans are encoded by the SYN1 gene. In its phosphorylated form, Synapsin I may also be referred to as phosphosynaspin I. Synapsin I is the first of the proteins in the synapsin family of phosphoproteins in the synaptic vesicles present in the central and peripheral nervous systems. Synapsin Ia and Ib are close in length and almost the same in make up, however, Synapsin Ib stops short of the last segment of the C-terminal in the amino acid sequence found in Synapsin Ia.

O-linked glycosylation is the attachment of a sugar molecule to the oxygen atom of serine (Ser) or threonine (Thr) residues in a protein. O-glycosylation is a post-translational modification that occurs after the protein has been synthesised. In eukaryotes, it occurs in the endoplasmic reticulum, Golgi apparatus and occasionally in the cytoplasm; in prokaryotes, it occurs in the cytoplasm. Several different sugars can be added to the serine or threonine, and they affect the protein in different ways by changing protein stability and regulating protein activity. O-glycans, which are the sugars added to the serine or threonine, have numerous functions throughout the body, including trafficking of cells in the immune system, allowing recognition of foreign material, controlling cell metabolism and providing cartilage and tendon flexibility. Because of the many functions they have, changes in O-glycosylation are important in many diseases including cancer, diabetes and Alzheimer's. O-glycosylation occurs in all domains of life, including eukaryotes, archaea and a number of pathogenic bacteria including Burkholderia cenocepacia, Neisseria gonorrhoeae and Acinetobacter baumannii.

Protein <i>O</i>-GlcNAc transferase Protein-coding gene in the species Homo sapiens

Protein O-GlcNAc transferase also known as OGT or O-linked N-acetylglucosaminyltransferase is an enzyme that in humans is encoded by the OGT gene. OGT catalyzes the addition of the O-GlcNAc post-translational modification to proteins.

Protein <i>O</i>-GlcNAcase Protein-coding gene in the species Homo sapiens

Protein O-GlcNAcase (EC 3.2.1.169, OGA, glycoside hydrolase O-GlcNAcase, O-GlcNAcase, BtGH84, O-GlcNAc hydrolase) is an enzyme with systematic name (protein)-3-O-(N-acetyl-D-glucosaminyl)-L-serine/threonine N-acetylglucosaminyl hydrolase. OGA is encoded by the OGA gene. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction:

  1. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-serine + H2O ⇌ [protein]-L-serine + N-acetyl-D-glucosamine
  2. [protein]-3-O-(N-acetyl-β-D-glucosaminyl)-L-threonine + H2O ⇌ [protein]-L-threonine + N-acetyl-D-glucosamine
<i>O</i>-GlcNAc

O-GlcNAc is a reversible enzymatic post-translational modification that is found on serine and threonine residues of nucleocytoplasmic proteins. The modification is characterized by a β-glycosidic bond between the hydroxyl group of serine or threonine side chains and N-acetylglucosamine (GlcNAc). O-GlcNAc differs from other forms of protein glycosylation: (i) O-GlcNAc is not elongated or modified to form more complex glycan structures, (ii) O-GlcNAc is almost exclusively found on nuclear and cytoplasmic proteins rather than membrane proteins and secretory proteins, and (iii) O-GlcNAc is a highly dynamic modification that turns over more rapidly than the proteins which it modifies. O-GlcNAc is conserved across metazoans.

References

  1. ↑ Finder, Expertise. "Linda Carol Hsieh-Wilson, California Institute of Technology: Learning and memory, Memory and motor control, Neurobiology • Expertise Finder Network". network.expertisefinder.com. Retrieved 2017-05-02.
  2. ↑ Hsieh-Wilson, L. C.; Schultz, P. G.; Stevens, R. C. (1996-05-28). "Insights into antibody catalysis: structure of an oxygenation catalyst at 1.9-angstrom resolution". Proceedings of the National Academy of Sciences of the United States of America. 93 (11): 5363–5367. Bibcode:1996PNAS...93.5363H. doi: 10.1073/pnas.93.11.5363 . PMC   39251 . PMID   8643580.
  3. ↑ Hsieh-Wilson, L. C.; Allen, P. B.; Watanabe, T.; Nairn, A. C.; Greengard, P. (1999-04-06). "Characterization of the neuronal targeting protein spinophilin and its interactions with protein phosphatase-1". Biochemistry. 38 (14): 4365–4373. doi:10.1021/bi982900m. PMID   10194355.
  4. ↑ Grossman, Stacie D.; Hsieh-Wilson, Linda C.; Allen, Patrick B.; Nairn, Angus C.; Greengard, Paul (2002-01-01). "The actin-binding domain of spinophilin is necessary and sufficient for targeting to dendritic spines". Neuromolecular Medicine. 2 (1): 61–69. doi:10.1385/NMM:2:1:61. PMID   12230305. S2CID   21825701.
  5. ↑ Hsieh-Wilson, Linda C.; Benfenati, Fabio; Snyder, Gretchen L.; Allen, Patrick B.; Nairn, Angus C.; Greengard, Paul (2003-01-10). "Phosphorylation of spinophilin modulates its interaction with actin filaments". The Journal of Biological Chemistry. 278 (2): 1186–1194. doi: 10.1074/jbc.M205754200 . PMID   12417592. S2CID   11557256.
  6. ↑ "Linda C. Hsieh-Wilson | www.cce.caltech.edu". www.cce.caltech.edu. Retrieved 2017-05-02.
  7. ↑ "HHMI Scientist Abstract: Linda C. Hsieh-Wilson, Ph.D." Howard Hughes Medical Institute. Retrieved 2011-07-16.
  8. ↑ Khidekel, Nelly; Ficarro, Scott B; Clark, Peter M; Bryan, Marian C; Swaney, Danielle L; Rexach, Jessica E; Sun, Yi E; Coon, Joshua J; et al. (2007). "Probing the dynamics of O-GlcNAc glycosylation in the brain using quantitative proteomics" (PDF). Nature Chemical Biology . 3 (6): 339–348. doi:10.1038/nchembio881. PMID   17496889.
  9. ↑ Gama, Cristal I; Tully, Sarah E; Sotogaku, Naoki; Clark, Peter M; Rawat, Manish; Vaidehi, Nagarajan; Goddard, William A; Nishi, Akinori; et al. (2006). "Sulfation patterns of glycosaminoglycans encode molecular recognition and activity" (PDF). Nature Chemical Biology. 2 (9): 467–473. doi:10.1038/nchembio810. PMID   16878128. S2CID   1229340.
  10. ↑ "Sweet Memories of Synapsins?". Science's STKE. 2006 (317): tw472. 2006. doi:10.1126/stke.3172006tw472. S2CID   220299653.
  11. ↑ Khidekel, Nelly; Ficarro, Scott B.; Peters, Eric C.; Hsieh-Wilson, Linda C. (7 September 2004). "Exploring the O-GlcNAc proteome: Direct identification of O-GlcNAc-modified proteins from the brain". Proceedings of the National Academy of Sciences. 101 (36): 13132–13137. Bibcode:2004PNAS..10113132K. doi: 10.1073/pnas.0403471101 . PMC   516536 . PMID   15340146.
  12. ↑ http://apps.webofknowledge.com/full_record.do?product=WOS&search_mode=DaisyOneClickSearch&qid=11&SID=1AMO2etzAYAIFJZoUSG&page=1&doc=6&cacheurlFromRightClick=no%5B%5D
  13. ↑ Hsieh-Wilson, Linda (2013-04-01). "O-GlcNAc Signaling Regulates Cancer Metabolism". The FASEB Journal. 27 (1 Supplement): 452.2. doi: 10.1096/fasebj.27.1_supplement.452.2 .
  14. ↑ http://apps.webofknowledge.com/full_record.do?product=WOS&search_mode=DaisyOneClickSearch&qid=11&SID=1AMO2etzAYAIFJZoUSG&page=1&doc=21%5B%5D
  15. ↑ Gama, Cristal I.; Tully, Sarah E.; Sotogaku, Naoki; Clark, Peter M.; Rawat, Manish; Vaidehi, Nagarajan; Goddard, William A.; Nishi, Akinori; Hsieh-Wilson, Linda C. (2006). "Sulfation patterns of glycosaminoglycans encode molecular recognition and activity". Nature Chemical Biology. 2 (9): 467–473. doi:10.1038/nchembio810. PMID   16878128. S2CID   1229340.
  16. ↑ Tully, Sarah E.; Mabon, Ross; Gama, Cristal I.; Tsai, Sherry M.; Liu, Xuewei; Hsieh-Wilson, Linda C. (2004-06-01). "A Chondroitin Sulfate Small Molecule that Stimulates Neuronal Growth" (PDF). Journal of the American Chemical Society. 126 (25): 7736–7737. doi:10.1021/ja0484045. ISSN   0002-7863. PMID   15212495.
  17. ↑ Shipp, Eric L.; Hsieh-Wilson, Linda C. (2007-02-01). "Profiling the Sulfation Specificities of Glycosaminoglycan Interactions with Growth Factors and Chemotactic Proteins Using Microarrays". Chemistry & Biology. 14 (2): 195–208. doi: 10.1016/j.chembiol.2006.12.009 . PMID   17317573.
  18. 1 2 "Web of Science". 2011. Retrieved 2011-07-16.
  19. ↑ "Linda C. Hsieh-Wilson". Arnold and Mabel Beckman Foundation. Retrieved 1 August 2018.
  20. ↑ "Arthur C. Cope Scholar Awards". American Chemical Society. Archived from the original on 2011-08-11. Retrieved 2011-07-16.
  21. ↑ "Top neuroscientists receive awards from IU's Gill Center". IU News Room. Indiana University. Retrieved 2019-09-15.
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