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  • Understanding the nature of protein collagen interactions is

    2020-08-07

    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 IWP-L6 synthesis 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 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.
    Transparency document
    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 Discoidin domain receptors (DDR1 and DDR2) are widely expressed receptor tyrosine kinases that regulate a variety of cellular processes including cell adhesion, differentiation, proliferation and migration [1], collagen fibrillogenesis [2], [3], [4], and remodeling of the extracellular matrix [5]. Collagen(s) is the only known ligand for DDRs [6]. Both the collagen binding domains of the receptors [7], [8], [9], [10] and their binding site on the collagen triple helix [11], [12], [13], [14] have been elucidated in recent years. In addition, it has been established that DDRs exist as constitutive homodimers on the cell membrane prior to collagen binding and receptor activation [15], [16], [17]. DDRs undergo slow and sustained receptor activation upon ligand binding. However, the reasons for the delayed kinetics of DDR phosphorylation upon ligand binding remain poorly defined. Receptor clustering or higher order receptor oligomerization has been postulated by us [16], [18] and others [17], [19], [20], [21] as important modulators of both DDR–collagen interaction and receptor phosphorylation.