Alternative splicing in the aggrecan G3 domain influences binding interactions with tenascin-C and other extracellular matrix proteins.
Open accessAbstract
The proteoglycans aggrecan, versican, neurocan, and brevican bind hyaluronan through their N-terminal G1 domains, and other extracellular matrix proteins through the C-type lectin repeat in their C-terminal G3 domains. Here we identify tenascin-C as a ligand for the lectins of all these proteoglycans and map the binding site on the tenascin molecule to fibronectin type III repeats, which corresponds to the proteoglycan lectin-binding site on tenascin-R. In the G3 domain, the C-type lectin is flanked by epidermal growth factor (EGF) repeats and a complement regulatory protein-like motif. In aggrecan, these are subject to alternative splicing. To investigate if these flanking modules affect the C-type lectin ligand interactions, we produced recombinant proteins corresponding to aggrecan G3 splice variants. The G3 variant proteins containing the C-type lectin showed different affinities for various ligands, including tenascin-C, tenascin-R, fibulin-1, and fibulin-2. The presence of an EGF motif enhanced the affinity of interaction, and in particular the splice variant containing both EGF motifs had significantly higher affinity for ligands, such as tenascin-R and fibulin-2. The mRNA for this splice variant was shown by reverse transcriptase-PCR to be expressed in human chondrocytes. Our findings suggest that alternative splicing in the aggrecan G3 domain may be a mechanism for modulating interactions and extracellular matrix assembly.
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Tenascins are fibrous, matricellular proteins that bind to the C-terminal domain of lecticans.
“Tenascins are fibrous, matricellular proteins, which bind to the C-terminal domain of lecticans (Aspberg et al., 1997; Day et al., 2004).”
From The Perineuronal ‘Safety’ Net? Perineuronal Net Abnormalities in Neurological Disorders (2018) · cites this paper as Day et al., 2004
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“G3 fragments contain lectin domains that would afford retention in the tissue via interaction with extracellular glycoproteins such as tenascin C (Day et al. 2004) and fibulin (Aspberg et al. 1999), and such fragments and ⁄ or their complexes may have region-specific bioactivities or structural…”
BackgroundWilson, C. G., Nishimuta, J. F., & Levenston, M. E. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2008.0106 · Cited by 53 · see citing works
“Aggrecan G3 contains lectin domains that can interact with other ECM molecules, such as tenascin- and fibulin-family proteins, and G3 fragments may be retained through these interactions.(35) It is possible that aggrecan G3 fragments can modulate the ECM organization, material properties, and biosynthetic activity of…”
Chockalingam, P. S., Glasson, S. S., & Lohmander, S. L. (2012) · Osteoarthritis and Cartilage · doi:10.1016/j.joca.2012.10.016 · Cited by 49 · see citing works
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Marx, G. S., & Gilon, C. (2012) · ACS Chemical Neuroscience · doi:10.1021/cn300097b · Cited by 45 · see citing works
Chondroitin sulfate proteoglycans in neural development and plasticity
Maeda, N. (2010) · Frontiers in Bioscience · doi:10.2741/3637 · Cited by 44 · see citing works
Impact of the complement cascade on posttraumatic cartilage inflammation and degradation.
John, T., Pf, S., Morgan, S. J., & Schulze-Tanzil, G. G. (2007) · PubMed · doi:10.14670/hh-22.781 · Cited by 43 · see citing works
“Other cartilage matrix proteoglycans contain lectin motifs or complement binding protein like domains which may be accessable during cartilage injury for complement activation via the lectin pathway (Chen et al., 2002; Day et al., 2004).”
BackgroundAnalysis of “old” proteins unmasks dynamic gradient of cartilage turnover in human limbs
Hsueh, M.-F., Önnerfjord, P., Bolognesi, M. P., Easley, M. E., & Kraus, V. B. (2019) · Science Advances · doi:10.1126/sciadv.aax3203 · Cited by 43 · see citing works
Xu, M., Stattin, E.-L., Shaw, G., Heinegård, D. K., Sullivan, G. J., Wilmut, I., Colman, A., Önnerfjord, P., Khabut, A., Aspberg, A., et al. (2016) · Stem Cells Translational Medicine · doi:10.5966/sctm.2015-0384 · Cited by 42 · see citing works
Self-citationHow do tenascins influence the birth and life of a malignant cell?
Brellier, F., & Chiquet‐Ehrismann, R. (2011) · Journal of Cellular and Molecular Medicine · doi:10.1111/j.1582-4934.2011.01360.x · Cited by 41 · see citing works
“For instance, through their binding to tenascin-C, fibronectin [78], perlecan [79], lectican [80], heparin [81], contactin [82, 83] and SMOC1 [84] have been shown to modify its effects.”
Hayes, A. J., Shu, C. C., Lord, M. S., Little, C. B., Whitelock, J. M., & Melrose, J. (2016) · European Cells and Materials · doi:10.22203/ecm.v032a03 · Cited by 40 · see citing works
Identification of proteoglycan from salmon nasal cartilage
Kakizaki, I., Tatara, Y., Majima, M., Kato, Y., & Endo, M. (2010) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2010.10.025 · Cited by 40 · see citing works
Potential biomarkers of the mature intervertebral disc identified at the single cell level
Li, K., Kapper, D., Youngs, B., Kocsis, V., Mondal, S., Kraus, P., & Lufkin, T. (2018) · Journal of Anatomy · doi:10.1111/joa.12904 · Cited by 38 · see citing works
Ishiyama, A., Mowry, S. E., López, I. A., & Ishiyama, G. P. (2009) · Hearing Research · doi:10.1016/j.heares.2009.03.014 · Cited by 37 · see citing works
“, 2007), proteoglycans (Day et al., 2004) and other ECM components.”
BackgroundBale, S., Verma, P., Varga, J., & Bhattacharyya, S. (2023) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2023.04.030 · Cited by 37 · see citing works
Tenascin-C fragments are endogenous inducers of cartilage matrix degradation
Sofat, N., Robertson, S. D., Hermansson, M., Jones, J. S., Mitchell, P., & Wait, R. (2011) · Rheumatology International · doi:10.1007/s00296-011-2067-8 · Cited by 36 · see citing works
Zacharias, U., & Rauch, U. (2006) · Journal of Cell Science · doi:10.1242/jcs.03094 · Cited by 35 · see citing works
“…tenascins and lecticans is mediated by protein-protein-interaction involving the fibronectin type III domains (FNIII domains) 4-5 of TN-R or tenascin-C and the C-type lectin domain of lecticans (Aspberg et al., 1997; Rauch et al., 1997; Milev et al., 1998; Day et al., 2004; Lundell et al., 2004).”
BackgroundKeller, K. E., Sun, Y. Y., Vranka, J. A., Hayashi, L., & Acott, T. S. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048523 · Cited by 35 · see citing works
“[40,41,42,43] In addition, we investigated bamacan (CSPG6), a CS-bearing proteoglycan that does not have a HA-binding link domain, [44] and SPARC, a matricellular protein that is highly expressed in the TM and enhances fibronectin assembly.”
Recombinant production of proteoglycans and their bioactive domains
Lord, M. S., & Whitelock, J. M. (2013) · FEBS Journal · doi:10.1111/febs.12197 · Cited by 34 · see citing works
The C-Type Lectin of the Aggrecan G3 Domain Activates Complement
Fürst, C. M., Mörgelin, M., Vadstrup, K., Heinegård, D. K., Aspberg, A., & Blom, A. M. (2013) · PLoS ONE · doi:10.1371/journal.pone.0061407 · Cited by 35 · see citing works
“The aggrecan G3 domain exists in different splice variants in man, with optional epidermal growth factor-like domains (EGF) and complement control protein (CCP) domain, which might finetune interactions between CLD and its ligands [17].”
InfluentialSelf-citationThe Tyrosine Sulfate Domain of Fibromodulin Binds Collagen and Enhances Fibril Formation
Tillgren, V., Mörgelin, M., Önnerfjord, P., Kalamajski, S., & Aspberg, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.730325 · Cited by 33 · see citing works
“Transfection of the construct into 293-EBNA cells (Invitrogen), selection with hygromycin, and purification of the secreted protein from culture medium by Ni(2) chelation affinity chromatography was as previously described (41).”
MethodSelf-citationRole of tenascin-C in articular cartilage
Hasegawa, M., Yoshida, T., & Sudo, A. (2017) · Modern Rheumatology · doi:10.1080/14397595.2017.1349560 · Cited by 33 · see citing works
“Whereas previous work has shown that the FNIII domains of TN-C are susceptible to proteolytic cleavage [45] and interact with ligands including integrins [43], they are also subject to heparin binding [46] and binding to other ECM molecules including fibronectin [47].”
BackgroundWilson, C. G., Vanderploeg, E. J., Zuo, F., Sandy, J. D., & Levenston, M. E. (2009) · Arthritis Research & Therapy · doi:10.1186/ar2862 · Cited by 33 · see citing works
“The G3 domain can bind ECM proteins such as fibulin and tenascin-C [54,55], and such interactions could facilitate retention of aggrecan in the meniscus.”
BackgroundLabrousse-Arias, D., Martı́nez-Ruiz, A., & Calzada, M. J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7275 · Cited by 31 · see citing works
Yang, L., Zhang, C., Wang, W., Wang, J., Xiao, Y., Lü, W., Ma, X., Chen, L., Ni, J., Wang, D., et al. (2018) · BMC Medical Genetics · doi:10.1186/s12881-018-0730-6 · Cited by 30 · see citing works
Rekad, Z., Izzi, V., Lamba, R., Ciais, D., & Obberghen‐Schilling, E. V. (2022) · Matrix Biology · doi:10.1016/j.matbio.2022.05.003 · Cited by 29 · see citing works
Jakovljević, A., Tucić, M., Blažíková, M., Korenić, A., Missirlis, Y. F., Stamenković, V., & Anđjus, P. R. (2021) · Cells · doi:10.3390/cells10061345 · Cited by 30 · see citing works
Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment
Fu, Z., Zhu, G., Luo, C., Chen, Z., Dou, Z., Chen, Y., Chen, Z., Su, S., & Liu, F. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.971462 · Cited by 28 · see citing works
“Additionally, TNC can bind to other ECM proteins, such as periostin (92), perlecan (93), fibrillin-2 (94), aggrecan (95), and SPARC-related modular calcium-binding protein 1 (SMOC1) (96).”
BackgroundApproaching the Proteoglycome: Molecular Interactions of Proteoglycans and Their Functional Output
Cattaruzza, S., & Perris, R. (2006) · Macromolecular Bioscience · doi:10.1002/mabi.200600100 · Cited by 27 · see citing works
Defining the versican interactome in lung health and disease
Tang, F., Brune, J. E., Chang, M. Y., Reeves, S. R., Altemeier, W. A., & Frevert, C. W. (2022) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00162.2022 · Cited by 25 · see citing works
Song, X., Li, X., Ge, Y., Song, J., Wei, Q., He, M., Wei, M., Zhang, Y., Chen, T., & Lin, Z. (2023) · International Immunopharmacology · doi:10.1016/j.intimp.2023.110718 · Cited by 24 · see citing works
Moffatt, P., Lee, E. R., St‐Jacques, B., Matsumoto, K., Yamaguchi, Y., & Roughley, P. J. (2011) · Developmental Dynamics · doi:10.1002/dvdy.22529 · Cited by 24 · see citing works
“…Col2-driven mice is not stably localized within the extracellular matrix by interaction with hyaluronan, but is localized by interaction of its G3 region with another matrix component (Day et al., 2004) or is undergoing continuous loss by diffusion and replacement by newly synthesized molecules.”
BackgroundDistribution and role of tenascin-C in human osteoarthritic cartilage
Nakoshi, Y., Hasegawa, M., Akeda, K., Iino, T., Sudo, A., Yoshida, T., & Uchida, A. (2010) · Journal of Orthopaedic Science · doi:10.1007/s00776-010-1513-x · Cited by 24 · see citing works
Sinha, A., Kawakami, J., Cole, K. S., Ladutska, A., Nguyen, M. Y., Zalmai, M. S., Holder, B. L., Broerman, V. M., Matthews, R. T., & Bouyain, S. (2023) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2023.104952 · Cited by 23 · see citing works
“The assay design was first validated by testing previously characterized interactions between RPTPζ and contactin-1 (CNTN1) (26, 27) and between TNC, TNR, and ACAN (28) as positive controls in two distinct “orientations”: Fc versus FcYTS and FcYTS versus Fc.”
MethodInfluentialTenascin-C restricts reactive astrogliosis in the ischemic brain
Dzyubenko, E., Manrique‐Castano, D., Pillath‐Eilers, M., Vasileiadou, P., Reinhard, J., Faissner, A., & Hermann, D. M. (2022) · Matrix Biology · doi:10.1016/j.matbio.2022.04.003 · Cited by 21 · see citing works
The Biology of Extracellular Matrix Proteins in Hypertrophic Scarring
Eremenko, E. E., Ding, J., Kwan, P. O., & Tredget, E. E. (2021) · Advances in Wound Care · doi:10.1089/wound.2020.1257 · Cited by 21 · see citing works
Fell‐Muir Lecture: Cartilage 2010 – The Known Unknowns
Hardingham, T. (2010) · International Journal of Experimental Pathology · doi:10.1111/j.1365-2613.2010.00719.x · Cited by 21 · see citing works
“The aggrecan G2 domain was shown to have no function in the formation of aggregates (Fosang & Hardingham 1989), but the G3 domain which includes a C-type lectin fold was shown to bind to several matrix molecules, including tenascins and fibulins (Day et al. 2004).”
BackgroundSelf-citationFrom expression pattern to genetic association in asthma and asthma-related phenotypes
Vaillancourt, V. T., Bordeleau, M., Laviolette, M., & Laprise, C. (2012) · BMC Research Notes · doi:10.1186/1756-0500-5-630 · Cited by 21 · see citing works
“The AGC1 gene, located in the chromosomal region 15q26, is coding for the aggrecan, a major component of the extracellular matrix of the cartilage that binds with tenascins [22].”
BackgroundEffects of covalently attached chondroitin sulfate on aggrecan cleavage by ADAMTS-4 and MMP-13
Miwa, H. E., Gerken, T. A., & Hering, T. M. (2006) · Matrix Biology · doi:10.1016/j.matbio.2006.07.004 · Cited by 21 · see citing works
Stattin, E., Lindblom, K., Struglics, A., Önnerfjord, P., Goldblatt, J., Dixit, A., Sarkar, A., Randell, T. L., Suri, M., Raggio, C., et al. (2022) · Scientific Reports · doi:10.1038/s41598-022-09211-y · Cited by 20 · see citing works
Self-citationRelevance of synovial fluid chondroitin sulphate as a biomarker to monitor polo pony joints.
Baccarin, R. Y. A., Rasera, L., Machado, T. S. L., & Michelacci, Y. M. C. D. S. (2014) · PubMed Central · Cited by 17 · see citing works
Fukuhara, Y., Cho, S. Y., Miyazaki, O., Hattori, A., Seo, J.-H., Mashima, R., Kosuga, M., Fukami, M., Jin, D., Okuyama, T., et al. (2018) · Clinical Dysmorphology · doi:10.1097/mcd.0000000000000241 · Cited by 17 · see citing works
“The CLD domain has a high affinity for extracellular matrix molecules, including tenascin-R, tenascin-C, fibulin-1, fibulin2, and fibrillin-1, and they interact with each other in a calcium-dependent manner (Aspberg et al., 1997; Rauch et al., 1997; Olin et al., 2001; Isogai et al., 2002; Day et al., 2004; Aspberg, 20…”
BackgroundProteoglycans of the Intervertebral Disc
Melrose, J., & Roughley, P. J. (2013) · Springer eBooks · doi:10.1007/978-3-7091-1535-0_4 · Cited by 17 · see citing works
FBLN1 promotes chondrocyte proliferation by increasing phosphorylation of Smad2
Xu, G., Geng, X., Yang, F., & Zhang, Y. (2021) · Journal of Orthopaedic Science · doi:10.1016/j.jos.2020.12.006 · Cited by 15 · see citing works
V3: an enigmatic isoform of the proteoglycan versican
Wight, T. N., Day, A. J., Kang, I., Harten, I. A., Kaber, G., Briggs, D. C., Braun, K. R., Lemire, J. M., Kinsella, M. G., Hinek, A., et al. (2023) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00059.2023 · Cited by 13 · see citing works
Enriched environment alters the behavioral profile of tenascin-C deficient mice
Stamenković, V., Milenkovic, I., Galjak, N., Todorović, V., & Anđjus, P. R. (2017) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.05.047 · Cited by 13 · see citing works
Calcium-dependent self-association of the C-type lectin domain of versican
Ney, A., Booms, P., Epple, G., Mörgelin, M., Guo, G., Kettelgerdes, G., Gessner, R. V., & Robinson, P. N. (2005) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/j.biocel.2005.07.007 · Cited by 12 · see citing works
Brain Interstitial Fluid Drainage Alterations in Glioma-Bearing Rats
Guan, X., Wang, W., Wang, A., Teng, Z., & Han, H. (2018) · Aging and Disease · doi:10.14336/ad.2017.0415 · Cited by 9 · see citing works
“Early studies reported that some of the matrix components excessively expressed with tumor growth and caused the tortuosity of the brain ECS were increased inside the tumor [9, 10].”
BackgroundAnalysis of Aggrecan Catabolism by Immunoblotting and Immunohistochemistry
Roughley, P. J., & Mort, J. S. (2011) · Methods in molecular biology · doi:10.1007/978-1-61779-498-8_15 · Cited by 9 · see citing works
Versican contributes to ligament formation of knee joints
Higuchi, T., Suzuki, D., Watanabe, T., Fanhchaksai, K., Ota, K., Yokoo, K., Furukawa, H., & Watanabe, H. (2021) · PLoS ONE · doi:10.1371/journal.pone.0250366 · Cited by 8 · see citing works
“The Cterminal G3 domain binds different ECM molecules such as fibrillin-1 [5], fibulin-1 and -2 [6, 7], tenascins [6, 8], and heparan sulfate proteoglycans [9].”
BackgroundProteoglycans and Diseases of Soft Tissues
Hwang, C. T., & Halper, J. T. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-3-030-80614-9_5 · Cited by 8 · see citing works
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Identification of Proteoglycan‐Binding Proteins
Muramatsu, T., Muramatsu, H., & Kojima, T. (2006) · Methods in enzymology on CD-ROM/Methods in enzymology · doi:10.1016/s0076-6879(06)16017-6 · Cited by 8 · see citing works
Collagen and Other Proteins of the Nucleus Pulposus, Annulus Fibrosus, and Cartilage End Plates
Mwale, F. (2013) · Springer eBooks · doi:10.1007/978-3-7091-1535-0_5 · Cited by 7 · see citing works
Jakovljević, A., Stamenković, V., Poleksić, J., Hamad, M. I. K., Reiss, G., Jakovčevski, I., & Anđjus, P. R. (2024) · Biomolecules · doi:10.3390/biom14040508 · Cited by 6 · see citing works
“TnC has been shown to interact with the major components of PNNs, aggrecan [63], neurocan, and phosphacan [64,65].”
BackgroundAPBP-1, a DNA/RNA-binding Protein, Interacts with the Chick Aggrecan Regulatory Region
Pirok, E. W., Domowicz, M. S., Henry, J. G., Wang, Y., Santore, M. T., Mueller, M. M., & Schwartz, N. B. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m505380200 · Cited by 6 · see citing works
Toscano, P., Meglio, L. D., Lonardo, F., Meglio, L. D., Mazzarelli, L. L., Sica, C., & Meglio, A. D. (2021) · BMC Pregnancy and Childbirth · doi:10.1186/s12884-021-03952-w · Cited by 5 · see citing works
Zhang, D., Liu, Z., Liu, Q., Lan, H., Peng, J., Liu, X., & Liu, W. (2021) · Inflammation · doi:10.1007/s10753-021-01540-w · Cited by 5 · see citing works
“TNC has a hexameric structure and many extracellular binding partners, including matrix components [28], soluble factors [29, 30], and pathogens as well as interactions with cell surface receptors such as TLR4 [21, 31].”
Background
- Authors
- Day, J. M., Olin, A. I., Murdoch, A. D., Canfield, A., Sasaki, T., Timpl, R., Hardingham, T. E., & Aspberg, A.
- Affiliations
- Wellcome Centre for Cell-Matrix Research (GB)
- Lund University (SE)
- Max Planck Institute of Biochemistry (DE)
- Corresponding author
- Aspberg, Anders
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2004-03
- Volume
- 279
- Issue
- 13
- Pages
- 12511-12518
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2157467821
- Cited by
- 127
- References
- 47
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 5 · 2023: 6 · 2022: 8 · 2021: 7 · 2020: 1 · 2019: 5 · 2018: 7 · 2017: 5 · 2016: 5 · 2015: 2 · 2014: 2 · 2013: 10 · 2012: 9
- FWCI
- 2.83
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Explorer (The University of Manchester) (publishedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Proteoglycans and glycosaminoglycans research
- Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Keywords
- aggrecan, alternative splicing, tenascin-C, tenascin-R, C-type lectin, EGF-like repeats, fibulin-1, fibulin-2, extracellular matrix assembly, chondrocytes, hyaluronan binding, fibronectin type III repeats
- MeSH terms
- Amino Acid Sequence, Base Sequence, Binding Sites, Binding, Competitive, Dose-Response Relationship, Drug, Electrophoresis, Polyacrylamide Gel, Epidermal Growth Factor, Extracellular Matrix, Fibronectins, Humans, Kinetics, Ligands, Molecular Sequence Data, Protein Binding, Proteoglycans, Recombinant Proteins, RNA, Messenger, Time Factors, Extracellular Matrix Proteins, Alternative Splicing, Protein Structure, Tertiary, Tenascin, Chondrocytes, Reverse Transcriptase Polymerase Chain Reaction, Surface Plasmon Resonance, Amino Acid Motifs, Lectins, Lectins, C-Type, Aggrecans
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