# Revealing Accessibility of Cryptic Protein Binding Sites within the Functional Collagen Fibril
## 5 Perspective  
### The Collagen Architecture as a \"Smart Fibril\": Regulating Accessibility of Partner Binding Sites  
The surface proposed by [PERSON] et al., placing the C-telopeptide on the fibril surface seems to be more accommodating of essential molecular interactions within the collagen fibril. The placement of the MMP cleavage site beneath the C-terminal D5 allows for the dynamics and motions of D5 to act as a gatekeeper, regulating the accessibility of the MMP binding and cleavage site [94]. MMP cleavage of the collagen fibril is critical for fibril turnover, tissue repair, and development. From the opposite perspective, this site would be buried deep within the fibril and be inaccessible for collagenolysis. Once degraded by MMPs, new interaction sites would become available in the cleaved collagen.  
With the C-telopeptide exposed, high affinity integrin binding sites are not accessible. However, the relative binding affinities for integrins were determined in fully exposed, triple helical peptides, and may not be translatable to the context of the complex assembly of the collagen fibril. Constant strong binding of integrin to the collagen fibril may not be optimal. Integrins aid in cell adhesion and movement along collagen, and if bound too tightly, cell movement may not be possible. It has been hypothesized that this tight regulation is biologically important as it limits platelet aggregation under \"healthy\" conditions but promotes firm platelet adhesion upon cellular activation caused by disruption of blood vessels [55; 58; 116; 117]. Using a ligand accessibility ranking system, [PERSON] et al. predicted integrin binding sites to be \"cryptic\", buried within the fibril assembly, and only partially accessible in the mature fibril [54]. They proposed that cell-collagen interactions are regulated by binding motifs being exposed only upon structural reorganization or degradation of the fibril [54]. Although the high affinity integrin-binding motif, GFOGER, on D3 is buried deep within the fibril, it may be accessible upon limited proteolysis or during fibril assembly [54; 94; 98].  
Of course, fibrils of different collagen types may have very different microfibrillar arrangements and binding interfaces. Relative affinities of integrin binding motifs and other interaction sequences of collagen binding partners have been largely determined via triple helical peptide binding studies on collagen II and III sequences. While these collagens share a high percentage of sequence identity, the similarities in arrangement into fibrillar structures have yet to be determined. A recent study by [PERSON] et al. reported on the adhesion of collagen-binding integrins in chondrocytes to a 8:1:1 mixture of collagens II, IX, and XI mimicking cartilage collagen [118]. They found that the chondrocytes adhered to triple helical collagen, but were bound only weakly to collagen in the fibrillar form. By immunoelectron microscopy, they observed recombinant integrin I-domains binding not directly to the collagen fibrils, but to residual non-fibrillar material peripheral to the fibrils [118]. While a previous study had observed the binding of integrins to collagen I fibrils, this recent study suggests that in cartilage collagen fibrils composed of collagens II, IX, and XI, integrins do not have access to their recognition sites.