Institute of Biochemistry, University of Cologne, Cologne, Germany.
Center for Biochemistry, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany.
Sci Rep. 2018 Nov 21;8(1):17187. doi: 10.1038/s41598-018-35447-8.
COMP (cartilage oligomeric matrix protein) is a member of the thrombospondin family and forms homopentamers as well as mixed heterooligomers with its closely related family member TSP-4. COMP is long known to bind to collagens and to influence collagen fibril formation. Recent work indicates that already intracellular interaction with collagen is important for collagen secretion. However, the exact binding site of COMP on the collagen triple helix has not been described up to now. In this study we have identified a GXKGHR motif on the collagen II helix to bind to COMP, using a recombinantly expressed collagen II peptide library. This binding sequence is conserved throughout evolution and we demonstrate that TSP-4 binds to the same sequence. The identified binding motif overlaps with the recognition sites of many other collagen-binding partners (e.g. PEDF, Heparin) and also spans the lysine residues, which form collagen cross-links. COMP might thereby protect collagen helices from premature modification and cross-linking. Interestingly, this motif is only found in classical fibrillar collagens, although COMP is known to also bind other types. This might indicate that COMP has a unique interface for fibrillar collagens, thus making it an interesting target for the development of antifibrotic drugs.
COMP（软骨寡聚基质蛋白）是血栓反应蛋白家族的一员，它形成同源五聚体以及与其密切相关的家族成员 TSP-4 的混合异源寡聚体。COMP 长期以来一直被认为与胶原蛋白结合，并影响胶原蛋白纤维的形成。最近的研究表明，胶原蛋白的细胞内相互作用对于胶原蛋白的分泌很重要。然而，到目前为止，COMP 在胶原蛋白三螺旋上的精确结合位点尚未被描述。在这项研究中，我们使用重组表达的胶原蛋白 II 肽文库，鉴定出在胶原蛋白 II 螺旋上与 COMP 结合的 GXKGHR 基序。该结合序列在整个进化过程中是保守的，我们证明 TSP-4 也与相同的序列结合。鉴定出的结合基序与许多其他胶原蛋白结合伙伴的识别位点重叠（例如 PEDF、肝素），并且跨越赖氨酸残基，这些残基形成胶原蛋白交联。COMP 可能因此保护胶原蛋白螺旋免受过早修饰和交联。有趣的是，尽管 COMP 已知还结合其他类型的胶原蛋白，但该基序仅存在于经典的纤维状胶原蛋白中。这可能表明 COMP 具有独特的纤维状胶原蛋白界面，因此成为抗纤维化药物开发的一个有趣的靶点。
