Transgenic Expression of Syndecan-1 Uncovers a Physiological Control of Feeding Behavior by Syndecan-3

Reizes, Ofer; Lincecum, John; Wang, Zihua; Goldberger, Olga; Huang, Li; Kaksonen, Marko; Ahima, Rexford S.; Hinkes, Michael T.; Barsh, Gregory S.; Rauvala, Heikki; Bernfield, Merton

doi:10.1016/s0092-8674(01)00415-9

Cited by 201 publications

(174 citation statements)

References 40 publications

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“…A recent paper (37) suggests that heparan sulfate proteoglycans may enhance the activity of AGRP in vivo, possibly by an interaction with the amino-terminal fragment. Physiological studies, nevertheless, demonstrate that the AGRP C-terminal domain alone is capable of exerting potent effects on energy balance.…”

Section: Discussionmentioning

confidence: 99%

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

et al. 2001

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The agouti-related protein (AGRP) is an endogenous antagonist of the melanocortin receptors MC3R and MC4R found in the hypothalamus and exhibits potent orexigenic (appetite-stimulating) activity. The cysteine-rich C-terminal domain of this protein, corresponding to AGRP(87-132), contains five disulfide bonds and exhibits receptor binding affinity and antagonism equivalent to that of the full-length protein. The three-dimensional structure of this domain has been determined by 1 H NMR at 800 MHz. The first 34 residues of AGRP(87-132) are well-ordered and contain a three-stranded antiparallel sheet, where the last two strands form a hairpin. The relative spatial positioning of the disulfide cross-links demonstrates that the ordered region of AGRP(87-132) adopts the inhibitor cystine knot (ICK) fold previously identified for numerous invertebrate toxins. Interestingly, this may be the first example of a mammalian protein assigned to the ICK superfamily. The hairpin's turn region presents a triplet of residues (Arg-Phe-Phe) known to be essential for melanocortin receptor binding. The structure also suggests that AGRP possesses an additional melanocortin-receptor contact region within a loop formed by the first 16 residues of its C-terminal domain. This specific region shows little sequence homology to the corresponding region of the agouti protein, which is an MC1R antagonist involved in pigmentation. Consideration of these sequence differences, along with recent experiments on mutant and chimeric melanocortin receptors, allows us to postulate that this loop in the first 16 residues of its C-terminal domain confers AGRP's distinct selectivity for MC3R and MC4R.Obesity and associated disorders such as diabetes are now at epidemic levels in the United States and other developed countries (1, 2). An understanding at the molecular level of the normal processes governing energy homeostasis and weight regulation is therefore essential for developing a comprehensive understanding of these disorders and producing effective pharmaceutical treatments. Recent studies have demonstrated the key role played by brain melanocortin receptors (MCRs) in the regulation of energy homeostasis (3-6). Although MCRs are found in various tissues, these studies indicate that the specific receptors MC3R and MC4R are directly implicated in energy balance. All MCRs are G-protein-coupled receptors (GPCRs) that up-regulate the production of cAMP in the presence of small endogenous peptide agonists (7). These agonists are derived in vivo from the single pro-opiomelanocortin peptide (POMC) that is cleaved post-translationally to form the melanocortinstimulating hormones (MSHs) and the adrenocorticotropin hormone (ACTH). MCR function is also modulated by potent endogenous antagonists known as the agouti protein and the agouti-related protein (AGRP) that indeed may exert even greater control over MCR signaling than the peptide agonists (8-11). Relative to the small peptide agonists, these antagonists are larger in size and possess a five-dis...

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Section: Discussionmentioning

confidence: 99%

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

et al. 2001

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“…30 HSPG is also linked to human obesity in Simpson-Golabi-Behmel overgrowth syndrome 31 and excessive weight gain in genetically engineered mice. 32 Knowledge of the role of GAGs in insulin signaling will be important in treating diabetes and understanding obesity. Small molecule based up-regulation and downregulation of this signaling might have therapeutic importance in the treatment of insulin-related diseases.…”

Section: Fgf Signal Transductionmentioning

confidence: 99%

Role of Glycosaminoglycans in Cellular Communication

2004

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Glycosaminoglycans are of critical importance in intercellular communication in organisms. This ubiquitous class of linear polyanions interacts with a wide variety of proteins, including growth factors and chemokines, which regulate important physiological processes. The presence of glycosaminoglycans on cell membranes and in the extracellular matrix also has resulted in their exploitation by infectious pathogens to gain access and entry into animal cells. This Account examines the structural and physical characteristics of these molecules responsible for their interaction with proteins important in cell-cell communication.

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“…HS play critical roles in a variety of biological interactions, including assisting viral infection, regulating blood coagulation and embryonic development, suppressing tumor growth, and controlling the eating behavior of mice by interacting with specific regulatory proteins (1)(2)(3)(4)(5). HS is initially synthesized as a copolymer of glucuronic acid and N-acetylated glucosamine by D-glucuronyl and N-acetyl-D-glucosaminyl transferase, followed by various modifications (6).…”

Section: -O-sulfotransferase Isoform 3 (3-ost-3) and It Provides Bimentioning

confidence: 99%

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Liu

Shriver

Pope

et al. 2002

Journal of Biological Chemistry

153

116

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Herpes simplex virus type 1 utilizes cell surface heparan sulfate as receptors to infect target cells. The unique heparan sulfate saccharide sequence offers the binding site for viral envelope proteins and plays critical roles in assisting viral infections. A specific 3-O-sulfated heparan sulfate is known to facilitate the entry of herpes simplex virus 1 into cells. The 3-O-sulfated heparan sulfate is generated by the heparan sulfate D-glucosaminyl-3-O-sulfotransferase isoform 3 (3-OST-3), and it provides binding sites for viral glycoprotein D (gD). Here, we report the purification and structural characterization of an oligosaccharide that binds to gD. The isolated gDbinding site is an octasaccharide, and has a binding affinity to gD around 18 M, as determined by affinity coelectrophoresis. The octasaccharide was prepared and purified from a heparan sulfate oligosaccharide library that was modified by purified 3-OST-3 enzyme. The molecular mass of the isolated octasaccharide was determined using both nanoelectrospray ionization mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry. The results from the sequence analysis suggest that the structure of the octasaccharide is a heptasulfated octasaccharide. The proposed structure of the octasaccharide is ⌬UA-GlcNSIdoUA2S-GlcNAc-UA2S-GlcNS-IdoUA2S-GlcNH 2 3S6S. Given that the binding of 3-O-sulfated heparan sulfate to gD can mediate viral entry, our results provide structural information about heparan sulfate-assisted viral entry.Heparan sulfates (HS), 1 highly sulfated polysaccharides, are present on the surface of mammalian cells and in the extracellular matrix in large quantities. HS play critical roles in a variety of biological interactions, including assisting viral infection, regulating blood coagulation and embryonic development, suppressing tumor growth, and controlling the eating behavior of mice by interacting with specific regulatory proteins (1-5). HS is initially synthesized as a copolymer of glucuronic acid and N-acetylated glucosamine by D-glucuronyl and N-acetyl-D-glucosaminyl transferase, followed by various modifications (6). These modifications include C 5 -epimerization of glucuronic acid to form iduronic acid residues, 2-O-sulfation of iduronic and glucuronic acid, N-deacetylation and N-sulfation of glucosamine, as well as 6-O-sulfation and 3-O-sulfation of glucosamine. Numerous HS biosynthetic enzymes have been cloned and characterized (for review, see Esko and Lindahl (7)).The specific sulfated saccharide sequences play critical roles in determining the functions of HS. A recent report suggests that the expression levels of various isoforms of each class of HS biosynthetic enzyme contribute to the synthesis of specific saccharide sequences in specific tissues (8). HS N-deacetylase/ N-sulfotransferase, 3-O-sulfotransferase, and 6-O-sulfotransferase are present in multiple isoforms, and each isoform is believed to recognize the saccharide sequence around the modification site to generate a specific sulfated saccharid...

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Transgenic Expression of Syndecan-1 Uncovers a Physiological Control of Feeding Behavior by Syndecan-3

Cited by 201 publications

References 40 publications

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

Role of Glycosaminoglycans in Cellular Communication

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

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Transgenic Expression of Syndecan-1 Uncovers a Physiological Control of Feeding Behavior by Syndecan-3

Cited by 201 publications

References 40 publications

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein,

Role of Glycosaminoglycans in Cellular Communication

Characterization of a Heparan Sulfate Octasaccharide That Binds to Herpes Simplex Virus Type 1 Glycoprotein D

Contact Info

Product

Resources

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High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,

High-Resolution NMR Structure of the Chemically-Synthesized Melanocortin Receptor Binding Domain AGRP(87−132) of the Agouti-Related Protein^,