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  • Understanding the nature of protein collagen interactions is


    Understanding the nature of protein–collagen interactions is also crucial in developing biomaterials that replicate the structural and biological characteristics of collagen [140]. These biomaterials can then be applied to develop scaffolds or tissues that can be valuable in surgeries or medicine [7,140]. These biomaterials can also incorporate synthetic adenosine deaminase and recombinant collagen, highlighting the adaptability of these tools. For example, chemically crosslinked collagen has been studied as a biomaterial in tissue engineering [140]. While this chemical treatment is important to create mechanically stable collagen film, it unfortunately disrupts the film\'s cell reactivity [141,142]. To restore reactivity to DDR2, a synthetic collagen-like peptide including the important DDR2-binding motif, (GPP)5-GPR-GQO-GVNle-GFO-(GPP)5, and a linker have been incorporated to crosslinked collagen films [143]. These crosslinked films coupled with the collagen-like peptide were then able to bind to DDR2 and induce DDR2 activation [143]. The recombinant Scl2 collagen system has shown capability as a biomaterial as well because of its adaptability and scalability. Scl2 was functionalized to crosslink into a hydrogel without disrupting its triple helix [130]. The Scl2–hydrogel crosslinking also did not disrupt cell adhesion and integrin binding when the α1 and α2 integrin binding motifs of collagen were inserted into the Scl2 [130]. This Scl2–hydrogel has been incorporated in the development of a vascular graft with suitable biomechanical properties [144] and in the development of an injectable medicine to stimulate chondrogenesis [145]. Additionally, a high-throughput batch purification methodology for adenosine deaminase Scl2 recombinant collagen has been developed [146]. This methodology has shown to be very scalable and produce a high percentage (>95%) of pure protein [146,147]. As our understanding of DDR–collagen interactions advances, it shall be possible to engineer biomaterials with DDR-activating or inhibiting properties.
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    Acknowledgements We thank Prof. Barbara Brodsky for valuable comments and discussion. We thank the support of the Tufts start-up fund and the Knez Family Faculty Investment Fund for Y.-S. L, and the Tufts Summer Scholar program for E.C.
    Introduction Collagen proteins, major components of extracellular matrix (ECM), play important roles in the regulation of cell function and behavior aside from the maintenance of tissue structure and integrity. The signals from extracellular collagens to the cells are transduced by specific cell-surface receptors, including integrins and discoidin domain receptors (DDRs) [1], [2]. DDRs, consisting of DDR1 and DDR2, belong to the receptor tyrosine kinase (RTK) subfamily and exhibit a slow but sustained phosphorylation kinetics in response to collagen binding [3]. DDR2 expression is mainly detected in mesenchymal-derived cells [4], [5]. Growing biological evidences have demonstrated that DDR2 can regulate cell proliferation, migration, differentiation, as well as extracellular matrix remodeling and epithelial-mesenchymal transition (EMT) [3], [6], [7], [8], [9], [10], [11], [12]. Upregulation of DDR2 signaling was reported to be associated with diverse human diseases, such as arthritis and cancer [13]. Elevated expression of matrix metalloproteinases (MMPs) that primarily mediate the degradation of ECM represents an important cell response to DDR2 activation [8], [14], [15]. However, up to date little is known as to how the DDR2 signaling is negatively regulated or attenuated.