Sulfation patterns of glycosaminoglycans encode molecular recognition and activity

Gama, Cristal I.; Tully, Sarah E.; Sotogaku, Naoki; Clark, Peter M.; Rawat, Diwan S.; Vaidehi, Nagarajan; Goddard, William A.; Nishi, Akinori; Hsieh‐Wilson, Linda C.

doi:10.1038/nchembio810

Cited by 510 publications

(512 citation statements)

References 33 publications

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“…Among the CS variants, CS-E and CS-D, which are highly sulfated, promote the outgrowth of neurites in embryonic mouse hippocampal neurons [23]. These two CS variants also show strong affinity to some growth factors, such as fibroblast growth factors and bone morphogenetic proteins (BMPs) [24,25]. CS-E enhances osteoblast differentiation by binding to BMP-4, which is an essential growth factor for chondrogenic differentiation [26].…”

Section: Discussionmentioning

confidence: 99%

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

Kawamura

Funakoshi

Mizumoto

et al. 2014

Journal of Orthopaedic Science

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Section: Discussionmentioning

confidence: 99%

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

Kawamura

Funakoshi

Mizumoto

et al. 2014

Journal of Orthopaedic Science

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“…It has been proposed that the sulfation pattern on the GAGs confers specific biological activity on axonal growth, either inhibiting (Gilbert et al, 2005;Properzi et al, 2005;Wang et al, 2008) or promoting (Gama et al, 2006;Lin et al, 2011) growth. The majority of CS-GAG sulfation in the mammalian central nervous system is found as disaccharides with a sulfate group on the 4 or 6 position of GalNAc (Ishii and Maeda, 2008;Kitagawa et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice

Katagiri

Susarla

et al. 2012

J of Comparative Neurology

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Chondroitin sulfate proteoglycans (CSPGs) play a pivotal role in many neuronal growth mechanisms including axon guidance and the modulation of repair processes following injury to the spinal cord or brain. Many actions of CSPGs in the central nervous system (CNS) are governed by the specific sulfation pattern on the glycosaminoglycan (GAG) chains attached to CSPG core proteins. To elucidate the role of CSPGs and sulfated GAG chains following traumatic brain injury (TBI), controlled cortical impact injury of mild to moderate severity was performed over the left sensory motor cortex in mice. Using immunoblotting and immunostaining, we found that TBI resulted in an increase in the CSPGs neurocan and NG2 expression in a tight band surrounding the injury core, which overlapped with the presence of 4-sulfated CS GAGs but not with 6-sulfated GAGs. This increase was observed as early as 7 days post injury (dpi), and persisted up to 28 dpi. Labeling with markers against microglia/macrophages, NG2 + cells, fibroblasts and astrocytes showed that these cells were all localized in the area, suggesting multiple origins of chondroitin-4-sultate increase. TBI also caused a decrease in the expression of aggrecan and phosphacan in the pericontusional cortex with a concomitant reduction in the number of perineuronal nets. In summary, we describe a dual response in CSPGs where they may be actively involved in complex repair processes following TBI. INDEXING TERMSChondroitin sulfate proteoglycan; traumatic brain injury; extracellular matrix; perineuronal nets

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“…Gama et al 2 addressing the highly complex problems being generated in glyco-biology. The current work is among the first to undertake structure-activity relationship experiments for synthetic saccharides using a combination of binding assays, biological assays and specific blocking antibodies.…”

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confidence: 99%

“…Induced-fit binding energies are often derived from distortion of the ligand and/or receptor, so the solution structures need to be extended to bound conformations with protein partners to be of predictive value. Additionally, further development of glycoarray techniques 2,4,5,8 is clearly necessary. The microarraying and protein-binding interrogation of synthetic CS oligosaccharides reported by Gama et al 2 is similar to that in use for synthetic heparins 5 and illustrates the utility of miniaturized interaction studies.…”

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confidence: 99%

“…The neurite outgrowth studies confirm the results obtained by Bao et al using libraries of natural saccharides 7 . Both groups also use blocking antibodies against selected epitopes 2,7 , and these tools should prove very useful for investigating epitope expression and function in vivo. The new study demonstrates that integration of diverse experimental platforms provides an effective approach for investigating the ways in which GAGs encode functional information in a sequence-specific manner 2 .…”

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confidence: 99%

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Synthetic sugars enhance the functional glycomics toolkit

Turnbull

Linhardt

2006

Nat Chem Biol

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Glycosaminoglycan-protein interactions are an important frontier for discovering new mechanisms of cellular regulation by complex sugars. The integration of the 'chemical glycomics' strategies of synthetic chemistry, arrays and biological assays shows that the precise pattern of sugar sulfation dictates the specificity of a sugar's function.Understanding the complex functions of the glycome-the repertoire of sugars expressed by cells, tissues and organisms-is a substantial challenge in the postgenome era. Glycosaminoglycans (GAGs) are an important class of complex sugars whose structurally diverse polysaccharide chains contain large amounts of information 1 that is linked to an extensive range of biological functions. However, an understanding of the mode of glycan specificity underlying these functions has proven elusive 1 . A paper by Gama et al. published in this issue of Nature Chemical Biology reports the synthesis of a set of chondroitin sulfate (CS) tetrasaccharides whose interactions and bioactivity provide evidence for a 'sulfation code' in which recognition of selected proteins is conferred by specific sequences 2 . The use of a unique combination of synthetic chemistry, microarray technology and biological assays indicates a way forward for future studies aimed at understanding the selectivity and functions of GAG structures.Questions concerning the specificity of GAG-protein interactions abound and can only be definitively addressed using fully characterized compounds. The difficulty of obtaining such structures from nature is a significant bottleneck, and the development of tools and technologies to evaluate these molecules lags behind that of genomics and proteomics. Fortunately, the field is rapidly changing 3 . For instance, chemical synthesis avoids many of the purification problems that plague natural-products chemistry. In addition, large-scale interrogation of glycan-proteins is now possible, allowing the discovery of new molecular liaisons. In particular, recent studies describe new approaches for obtaining arrayed displays of both natural 4 and synthetic 5 GAG structures from the heparan sulfate-heparin family.Initial efforts in glycosynthesis, such as those by Lopin et al., demonstrated that chondroitin saccharides can be effectively synthesized in a highly convergent and efficient manner 6 . Gama et al. 2 extend these concepts by emphasizing the value of integrative science in NIH Public Access

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Sulfation patterns of glycosaminoglycans encode molecular recognition and activity

Cited by 510 publications

References 33 publications

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

Sulfation patterns of exogenous chondroitin sulfate affect chondrogenic differentiation of ATDC5 cells

Alterations in sulfated chondroitin glycosaminoglycans following controlled cortical impact injury in mice

Synthetic sugars enhance the functional glycomics toolkit

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