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    • Various domains of DDR have been shown to

    2020-08-07

    Various domains of DDR1 have been shown to be important for receptor clustering and its oligomeric status. It is now understood that (i) dimerization [7] and higher-order oligomerization [12], [18] of the DDR1 extracellular domain (ECD) enhance its binding to collagen; (ii) DDR1 exists as non-covalent homodimer on the cell surface, which is mediated by critical residues within its ECD [17] and transmembrane domain (TMD) [15]; (iii) both full-length and kinase-dead DDR1 expressed on the cell surface undergo clustering upon collagen binding [16], [17], [18], [20], [21]; and (iv) clustering of DDR1 post-ligand binding is mediated in part by its ECD [18] and by its intracellular domain (ICD) [20], [21]. DDR1 clustering has been postulated to be a mechanism required for receptor activation based on our earlier microscopy-based studies [16], [18], X-ray crystallographic insights by Carafoli et al. [10] and recent cell-based studies [20]. In this regard, mutation of an N-glycosylation site in the DDR1 ECD (which results in a higher population of dimers) has been shown to induce ligand-independent activation of DDR1 [17]. In another study, a function-blocking monoclonal antibody, which binds to DDR1 ECD and inhibits collagen-induced receptor phosphorylation [10], also inhibited DDR1 clustering [21]. Thus, understanding the structural constrains and molecular mechanisms that promote the clustering and/or the oligomeric state of DDR1 could be exploited as a therapeutic avenue to modulate receptor function in diseases involving DDR1 activity. In vx 20 to DDR1, the role of oligomerization and/or clustering of DDR2 in mediating its interactions with collagen is less understood. Current data show that in DDR2, like in DDR1, (i) dimerization [7] and higher-order oligomerization of its ECD [11], [22] enhance its binding to collagen, and (ii) in cells, DDR2 exists as a constitutive non-covalent homodimer [15], which is partly promoted by high propensity of the TMD of DDR2 to self-interact [23]. A juxtamembrane segment in the ICD of DDR2 has also been shown to control receptor dimerization and thereby regulate collagen-dependent activation [24]. However, studies on DDR2 clustering, spatial distribution and its correlation with receptor phosphorylation post-ligand binding are lacking.
    Materials and Methods
    Results Using surface plasmon resonance, we previously demonstrated that oligomeric forms of DDR2-Fc displayed enhanced ability to bind bovine-dermal collagen I when compared to dimeric forms of DDR2-Fc [22]. In addition, in separate studies, we showed that monomeric DDR2-V5-His [2], dimeric DDR2-Fc [25], and oligomeric DDR2-Fc [22] forms could all inhibit collagen I fibrillogenesis. However, in these earlier studies, the relative abilities of these structural states of the DDR2 ECD could not be compared side by side because of the different experimental conditions used. Here, under identical experimental conditions, we examined the relative abilities of the DDR2 ECD, in its various oligomeric states, to bind to soluble collagen I and modulate its fibrillogenesis. Studies were conducted using telopeptide-lacking bovine-dermal collagen as well as telopeptide-containing rat-tail collagen I.