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Elucidating glycosaminoglycan–protein–protein interactions using carbohydrate microarray and computational approaches

Rogers, Claude J. and Clark, Peter M. and Tully, Sarah E. and Abrol, Ravinder and Garcia, K. Christopher and Goddard, William A., III and Hsieh-Wilson, Linda C. (2011) Elucidating glycosaminoglycan–protein–protein interactions using carbohydrate microarray and computational approaches. Proceedings of the National Academy of Sciences of the United States of America, 108 (24). pp. 9747-9752. ISSN 0027-8424. PMCID PMC3116396. https://resolver.caltech.edu/CaltechAUTHORS:20110627-141615339

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Abstract

Glycosaminoglycan polysaccharides play critical roles in many cellular processes, ranging from viral invasion and angiogenesis to spinal cord injury. Their diverse biological activities are derived from an ability to regulate a remarkable number of proteins. However, few methods exist for the rapid identification of glycosaminoglycan–protein interactions and for studying the potential of glycosaminoglycans to assemble multimeric protein complexes. Here, we report a multidisciplinary approach that combines new carbohydrate microarray and computational modeling methodologies to elucidate glycosaminoglycan–protein interactions. The approach was validated through the study of known protein partners for heparan and chondroitin sulfate, including fibroblast growth factor 2 (FGF2) and its receptor FGFR1, the malarial protein VAR2CSA, and tumor necrosis factor-α (TNF-α). We also applied the approach to identify previously undescribed interactions between a specific sulfated epitope on chondroitin sulfate, CS-E, and the neurotrophins, a critical family of growth factors involved in the development, maintenance, and survival of the vertebrate nervous system. Our studies show for the first time that CS is capable of assembling multimeric signaling complexes and modulating neurotrophin signaling pathways. In addition, we identify a contiguous CS-E-binding site by computational modeling that suggests a potential mechanism to explain how CS may promote neurotrophin-tyrosine receptor kinase (Trk) complex formation and neurotrophin signaling. Together, our combined microarray and computational modeling methodologies provide a general, facile means to identify new glycosaminoglycan–protein–protein interactions, as well as a molecular-level understanding of those complexes.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1073/pnas.1102962108DOIArticle
http://www.pnas.org/content/108/24/9747PublisherArticle
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3116396/PubMed CentralArticle
ORCID:
AuthorORCID
Abrol, Ravinder0000-0001-7333-6793
Garcia, K. Christopher0000-0001-9273-0278
Goddard, William A., III0000-0003-0097-5716
Hsieh-Wilson, Linda C.0000-0001-5661-1714
Additional Information:© 2011 National Academy of Sciences. Edited by Chi-Huey Wong, Academia Sinica, Taipei, Taiwan, and approved May 4, 2011 (received for review February 25, 2011). Published online before print May 31, 2011. We thank Dr. Jose Luis Riechmann, Dr. Igor Antoshechkin, and the Caltech Millard and Muriel Jacobs Genetics and Genomics Laboratory for assistance and instrumentation for the microarray studies. We also thank Dr. Nagarajan Vaidehi, Adam Griffith, and other members of the Goddard group for their assistance. This work was supported by National Institutes of Health Grants R01 GM093627 (to L.H.W.), Training Grant 5T32 GM07616 (to C.J.R.), Training Grant 5T32 GM07737 (to P.M.C.), R01 NS071112 and 1R01 NS073115 (to W.A.G.), and by a National Science Foundation Predoctoral Fellowship (to S.E.T.). Author contributions: C.J.R., P.M.C., R.A., W.A.G., and L.C.H.-W. designed research; C.J.R., P.M.C., and S.E.T. performed research; C.J.R., P.M.C., S.E.T., and K.C.G. contributed new reagents/analytic tools; C.J.R., P.M.C., R.A., W.A.G., and L.C.H.-W. analyzed data; and C.J.R., P.M.C., and L.C.H.-W. wrote the paper.
Funders:
Funding AgencyGrant Number
NIHR01 GM093627
NIH5T32 GM07616
NIH5T32 GM07737
NIHR01 NS071112
NIH1R01 NS073115
NSF Predoctoral FellowshipUNSPECIFIED
Issue or Number:24
PubMed Central ID:PMC3116396
Record Number:CaltechAUTHORS:20110627-141615339
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20110627-141615339
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:24228
Collection:CaltechAUTHORS
Deposited By: Jason Perez
Deposited On:27 Jun 2011 22:27
Last Modified:03 Oct 2019 02:54

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