Molecular Tissue Responses to Mechanical Loading.

The intention of this special edition is to highlight the benefits of a holistic approach to computational and experimental approaches in the context of aiding the diagnosis and remediation of disease and injury, especially in neurological and connective tissues and organs [...].

Contrasting Local and Macroscopic Effects of Collagen Hydroxylation.

Collagen is heavily hydroxylated. Experiments show that proline hydroxylation is important to triple helix (monomer) stability, fibril assembly, and interaction of fibrils with other molecules. Nevertheless, experiments also show that even without hydroxylation, type I collagen does assemble into its native D-banded fibrillar structure. This raises two questions. Firstly, even though hydroxylation removal marginally affects macroscopic structure, how does such an extensive chemical change, which is expected to substantially reduce hydrogen bonding capacity, affect local structure? Secondly, how does such a chemical perturbation, which is expected to substantially decrease electrostatic attraction between monomers, affect collagen's mechanical properties? To address these issues, we conduct a benchmarked molecular dynamics study of rat type I fibrils in the presence and absence of hydroxylation. Our simulations reproduce the experimental observation that hydroxylation removal has a minimal effect on collagen's D-band length. We also find that the gap-overlap ratio, monomer width and monomer length are minimally affected. Surprisingly, we find that de-hydroxylation also has a minor effect on the fibril's Young's modulus, and elastic stress build up is also accompanied by tightening of triple-helix windings. In terms of local structure, de-hydroxylation does result in a substantial drop (23%) in inter-monomer hydrogen bonding. However, at the same time, the local structures and inter-monomer hydrogen bonding networks of non-hydroxylated amino acids are also affected. It seems that it is this intrinsic plasticity in inter-monomer interactions that preclude fibrils from undergoing any large changes in macroscopic properties. Nevertheless, changes in local structure can be expected to directly impact collagen's interaction with extra-cellular matrix proteins. In general, this study highlights a key challenge in tissue engineering and medicine related to mapping collagen chemistry to macroscopic properties but suggests a path forward to address it using molecular dynamics simulations.

Advanced Methodology and Preliminary Measurements of Molecular and Mechanical Properties of Heart Valves under Dynamic Strain.

Mammalian heart valves are soft tissue assemblies with multi-scale material properties. This is because they are constructs comprising both muscle and non-contractile extracellular matrix proteins (such as collagens and proteoglycans) and transition regions where one form of tissue structure becomes another, significantly different form. The leaflets of the mitral and tricuspid valves are connected to chordae tendinae which, in turn, bind through papillary muscles to the cardiac wall of the ventricle. The transition regions between these tissue subsets are complex and diffuse. Their material composition and mechanical properties have not been previously described with both micro and nanoscopic data recorded simultaneously, as reported here. Annotating the mechanical characteristics of these tissue transitions will be of great value in developing novel implants, improving the state of the surgical simulators and advancing robot-assisted surgery. We present here developments in multi-scale methodology that produce data that can relate mechanical properties to molecular structure using scanning X-ray diffraction. We correlate these data to corresponding tissue level (macro and microscopic) stress and strain, with particular emphasis on the transition regions and present analyses to indicate points of possible failure in these tissues.

Functional Grading of a Transversely Isotropic Hyperelastic Model with Applications in Modeling Tricuspid and Mitral Valve Transition Regions.

Surgical simulators and injury-prediction human models require a combination of representative tissue geometry and accurate tissue material properties to predict realistic tool-tissue interaction forces and injury mechanisms, respectively. While biological tissues have been individually characterized, the transition regions between tissues have received limited research attention, potentially resulting in inaccuracies within simulations. In this work, an approach to characterize the transition regions in transversely isotropic (TI) soft tissues using functionally graded material (FGM) modeling is presented. The effect of nonlinearities and multi-regime nature of the TI model on the functional grading process is discussed. The proposed approach has been implemented to characterize the transition regions in the leaflet (LL), chordae tendinae (CT) and the papillary muscle (PM) of porcine tricuspid valve (TV) and mitral valve (MV). The FGM model is informed using high resolution morphological measurements of the collagen fiber orientation and tissue composition in the transition regions, and deformation characteristics predicted by the FGM model are numerically validated to experimental data using X-ray diffraction imaging. The results indicate feasibility of using the FGM approach in modeling soft-tissue transitions and has implications in improving physical representation of tissue deformation throughout the body using a scalable version of the proposed approach.

Ultrastructural Location and Interactions of the Immunoglobulin Receptor Binding Sequence within Fibrillar Type I Collagen.

Collagen type I is a major constituent of animal bodies. It is found in large quantities in tendon, bone, skin, cartilage, blood vessels, bronchi, and the lung interstitium. It is also produced and accumulates in large amounts in response to certain inflammations such as lung fibrosis. Our understanding of the molecular organization of fibrillar collagen and cellular interaction motifs, such as those involved with immune-associated molecules, continues to be refined. In this study, antibodies raised against type I collagen were used to label intact D-periodic type I collagen fibrils and observed with atomic force microscopy (AFM), and X-ray diffraction (XRD) and immunolabeling positions were observed with both methods. The antibodies bind close to the C-terminal telopeptide which verifies the location and accessibility of both the major histocompatibility complex (MHC) class I (MHCI) binding domain and C-terminal telopeptide on the outside of the collagen fibril. The close proximity of the C-telopeptide and the MHC1 domain of type I collagen to fibronectin, discoidin domain receptor (DDR), and collagenase cleavage domains likely facilitate the interaction of ligands and receptors related to cellular immunity and the collagen-based Extracellular Matrix.

X-ray diffraction reveals blunt-force loading threshold for nanoscopic structural change in ex vivo neuronal tissues.

An ex vivo blunt-force loading experiment is reported that may, in the future, provide insight into the molecular structural changes occurring in load-induced conditions such as traumatic brain injury (TBI). TBI appears to manifest in changes in multiple structures and elements within the brain and nervous system. Individuals with a TBI may suffer from cognitive and/or behavioral impairments which can adversely affect their quality of life. Information on the injury threshold of tissue loading for mammalian neurons is critical in the development of a quantified neuronal-level dose-response model. Such a model could aid in the discovery of enhanced methods for TBI detection, treatment and prevention. Currently, thresholds of mechanical load leading to direct force-coupled nanostructural changes in neurons are unknown. In this study, we make use of the fact that changes in the structure and periodicity of myelin may indicate neurological damage and can be detected with X-ray diffraction (XRD). XRD allows access to a nanoscopic resolution range not readily achieved by alternative methods, nor does the experimental methodology require chemical sample fixation. In this study, XRD was used to evaluate the affects of controlled mechanical loading on myelin packing structure in ex vivo optic nerve samples. By using a series of crush tests on isolated optic nerves a quantified baseline for mechanical load was found to induce changes in the packing structure of myelin. To the authors' knowledge, this is the first report of its kind.

Molecular and ultrastructural studies of a fibrillar collagen from octocoral (Cnidaria).

We report here the biochemical, molecular and ultrastructural features of a unique organization of fibrillar collagen extracted from the octocoral Sarcophyton ehrenbergi Collagen, the most abundant protein in the animal kingdom, is often defined as a structural component of extracellular matrices in metazoans. In the present study, collagen fibers were extracted from the mesenteries of S. ehrenbergi polyps. These fibers are organized as filaments and further compacted as coiled fibers. The fibers are uniquely long, reaching an unprecedented length of tens of centimeters. The diameter of these fibers is 9±0.37 µm. The amino acid content of these fibers was identified using chromatography and revealed close similarity in content to mammalian type I and II collagens. The ultrastructural organization of the fibers was characterized by means of high-resolution microscopy and X-ray diffraction. The fibers are composed of fibrils and fibril bundles in the range of 15 to 35 nm. These data indicate a fibrillar collagen possessing structural aspects of both types I and II collagen, a highly interesting and newly described form of fibrillar collagen organization.

Nanomechanics of Type I Collagen.

Type I collagen is the predominant collagen in mature tendons and ligaments, where it gives them their load-bearing mechanical properties. Fibrils of type I collagen are formed by the packing of polypeptide triple helices. Higher-order structures like fibril bundles and fibers are assembled from fibrils in the presence of other collagenous molecules and noncollagenous molecules. Curiously, however, experiments show that fibrils/fibril bundles are less resistant to axial stress compared to their constituent triple helices-the Young's moduli of fibrils/fibril bundles are an order-of-magnitude smaller than the Young's moduli of triple helices. Given the sensitivity of the Young's moduli of triple helices to solvation environment, a plausible explanation is that the packing of triple helices into fibrils perhaps reduces the Young's modulus of an individual triple helix, which results in fibrils having smaller Young's moduli. We find, however, from molecular dynamics and accelerated conformational sampling simulations that the Young's modulus of the buried core of the fibril is of the same order as that of a triple helix in aqueous phase. These simulations, therefore, suggest that the lower Young's moduli of fibrils/fibril bundles cannot be attributed to the specific packing of triple helices in the fibril core. It is not the fibril core that yields initially to axial stress. Rather, it must be the portion of the fibril exposed to the solvent and/or the fibril-fibril interface that bears the initial strain. Overall, this work provides estimates of Young's moduli and persistence lengths at two levels of collagen's structural assembly, which are necessary to quantitatively investigate the response of various biological factors on collagen mechanics, including congenital mutations, posttranslational modifications and ligand binding, and also engineer new collagen-based materials.

Molecular composition and function of integrin-based collagen glues-introducing COLINBRIs.

BACKGROUND: Despite detailed knowledge about the structure and signaling properties of individual collagen receptors, much remains to be learned about how these receptors participate in linking cells to fibrillar collagen matrices in tissues. In addition to collagen-binding integrins, a group of proteins with affinity both for fibrillar collagens and integrins link these two protein families together. We have introduced the name COLINBRI (COLlagen INtegrin BRIdging) for this set of molecules. Whereas collagens are the major building blocks in tissues and defects in these structural proteins have severe consequences for tissue integrity, the mild phenotypes of the integrin type of collagen receptors have raised questions about their importance in tissue biology and pathology. SCOPE OF REVIEW: We will discuss the two types of cell linkages to fibrillar collagen (direct- versus indirect COLINBRI-mediated) and discuss how the parallel existence of direct and indirect linkages to collagens may ensure tissue integrity. MAJOR CONCLUSIONS: The observed mild phenotypes of mice deficient in collagen-binding integrins and the relatively restricted availability of integrin-binding sequences in mature fibrillar collagen matrices support the existence of indirect collagen-binding mechanisms in parallel with direct collagen binding in vivo. GENERAL SIGNIFICANCE: A continued focus on understanding the molecular details of cell adhesion mechanisms to collagens will be important and will benefit our understanding of diseases like tissue- and tumor fibrosis where collagen dynamics are disturbed. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties.

Effect of intrinsic and extrinsic factors on the simulated D-band length of type I collagen.

A signature feature of collagen is its axial periodicity visible in TEM as alternating dark and light bands. In mature, type I collagen, this repeating unit, D, is 67 nm long. This periodicity reflects an underlying packing of constituent triple-helix polypeptide monomers wherein the dark bands represent gaps between axially adjacent monomers. This organization is visible distinctly in the microfibrillar model of collagen obtained from fiber diffraction. However, to date, no atomistic simulations of this diffraction model under zero-stress conditions have reported a preservation of this structural feature. Such a demonstration is important as it provides the baseline to infer response functions of physiological stimuli. In contrast, simulations predict a considerable shrinkage of the D-band (11-19%). Here we evaluate systemically the effect of several factors on D-band shrinkage. Using force fields employed in previous studies we find that irrespective of the temperature/pressure coupling algorithms, assumed salt concentration or hydration level, and whether or not the monomers are cross-linked, the D-band shrinks considerably. This shrinkage is associated with the bending and widening of individual monomers, but employing a force field whose backbone dihedral energy landscape matches more closely with our computed CCSD(T) values produces a small D-band shrinkage of < 3%. Since this force field also performs better against other experimental data, it appears that the large shrinkage observed in earlier simulations is a force-field artifact. The residual shrinkage could be due to the absence of certain atomic-level details, such as glycosylation sites, for which we do not yet have suitable data.

Assessing Heterogeneity in the N-Telopeptides of Type I Collagen by Mass Spectrometry.

Collagen cross-links created by the lysyl oxidase and lysyl hydroxylase families of enzymes are a significant contributing factor to the biomechanical strength and rigidity of tissues, which in turn influence cell signaling and ultimately cell phenotype. In the clinic, the proteolytically liberated N-terminal cross-linked peptide of collagen I (NTX) is used as a biomarker of bone and connective tissue turnover, which is altered in several disease processes. Despite the clinical utility of these collagen breakdown products, the majority of the cross-linked peptide species have not been identified in proteomic datasets. Here we evaluate several parameters for the preparation and identification of these peptides from the collagen I-rich Achilles tendon. Our refined approach involving chemical digestion for protein solubilization coupled with mass spectrometry allows for the identification of the NTX cross-links in a range of modification states. Based on the specificity of the enzymatic cross-linking reaction we utilized follow-up variable modification searches to facilitate identification with a wider range of analytical workflows. We then applied a spectral library approach to identify differences in collagen cross-links in bovine pulmonary hypertension. The presented method offers unique opportunities to understand extracellular matrix remodeling events in development, aging, wound healing, and fibrotic disease that modulate collagen architecture through lysyl-hydroxylase and lysyl-oxidase enzymes.

X-ray diffraction study of nanocrystalline and amorphous structure within major and minor ampullate dragline spider silks.

Synchrotron X-ray micro-diffraction experiments were carried out on Nephila clavipes (NC) and Argiope aurantia (AA) major (MA) and minor ampullate (MiA) fibers that make up dragline spider silk. The diffraction patterns show a semi-crystalline structure with ß-poly(l-alanine) nanocrystallites embedded in a partially oriented amorphous matrix. A superlattice reflection 'S' diffraction ring is observed, which corresponds to a crystalline component larger in size and is poorly oriented, when compared to the ß-poly(l-alanine) nanocrystallites that are commonly observed in dragline spider silks. Crystallite size, crystallinity and orientation about the fiber axis have been determined from the wide-angle X-ray diffraction (WAXD) patterns. In both NC and AA, the MiA silks are found to be more highly crystalline, when compared with the corresponding MA silks. Detailed analysis on the amorphous matrix shows considerable differences in the degree of order of the oriented amorphous component between the different silks studied and may play a crucial role in determining the mechanical properties of the silks.

The Japanese mutant Aß (ΔE22-Aß(1-39)) forms fibrils instantaneously, with low-thioflavin T fluorescence: seeding of wild-type Aß(1-40) into atypical fibrils by ΔE22-Aß(1-39).

The ΔE693 (Japanese) mutation of the ß-amyloid precursor protein leads to production of ΔE22-Aß peptides such as ΔE22-Aß(1-39). Despite reports that these peptides do not form fibrils, here we show that, on the contrary, the peptide forms fibrils essentially instantaneously. The fibrils are typical amyloid fibrils in all respects except that they cause only low levels of thioflavin T (ThT) fluorescence, which, however, develops with no lag phase. The fibrils bind ThT, but with a lower affinity and a smaller number of binding sites than wild-type (WT) Aß(1-40). Fluorescence depolarization confirms extremely rapid aggregation of ΔE22-Aß(1-39). Size exclusion chromatography (SEC) indicates very low concentrations of soluble monomer and oligomer, but only in the presence of some organic solvent, e.g., 2% (v/v) DMSO. The critical concentration is approximately 1 order of magnitude lower for ΔE22-Aß(1-39) than for WT Aß(1-40). Several lines of evidence point to an altered structure for ΔE22-Aß(1-39) compared to that of WT Aß(1-40) fibrils. In addition to differences in ThT binding and fluorescence, PITHIRDS-CT solid-state nuclear magnetic resonance (NMR) measurements of ΔE22-Aß(1-39) are not compatible with the parallel in-register ß-sheet generally observed for WT Aß(1-40) fibrils. X-ray fibril diffraction showed different D spacings: 4.7 and 10.4 Å for WT Aß(1-40) and 4.7 and 9.6 Å for ΔE22-Aß(1-39). Equimolar mixtures of ΔE22-Aß(1-39) and WT Aß(1-40) also produced fibrils extremely rapidly, and by the criteria of ThT fluorescence and electron microscopic appearance, they were the same as fibrils made from pure ΔE22-Aß(1-39). X-ray diffraction of fibrils formed from 1:1 molar mixtures of ΔE22-Aß(1-39) and WT Aß(1-40) showed the same D spacings as fibrils of the pure mutant peptide, not the wild-type peptide. These findings are consistent with extremely rapid nucleation by ΔE22-Aß(1-39), followed by fibril extension by WT Aß(1-40), and "conversion" of the wild-type peptide to a structure similar to that of the mutant peptide, in a manner reminiscent of the prion conversion phenomenon.

In situ D-periodic molecular structure of type II collagen.

Collagens are essential components of extracellular matrices in multicellular animals. Fibrillar type II collagen is the most prominent component of articular cartilage and other cartilage-like tissues such as notochord. Its in situ macromolecular and packing structures have not been fully characterized, but an understanding of these attributes may help reveal mechanisms of tissue assembly and degradation (as in osteo- and rheumatoid arthritis). In some tissues such as lamprey notochord, the collagen fibrillar organization is naturally crystalline and may be studied by x-ray diffraction. We used diffraction data from native and derivative notochord tissue samples to solve the axial, D-periodic structure of type II collagen via multiple isomorphous replacement. The electron density maps and heavy atom data revealed the conformation of the nonhelical telopeptides and the overall D-periodic structure of collagen type II in native tissues, data that were further supported by structure prediction and transmission electron microscopy. These results help to explain the observed differences in collagen type I and type II fibrillar architecture and indicate the collagen type II cross-link organization, which is crucial for fibrillogenesis. Transmission electron microscopy data show the close relationship between lamprey and mammalian collagen fibrils, even though the respective larger scale tissue architecture differs.

Collagen fibril architecture, domain organization, and triple-helical conformation govern its proteolysis.

We describe the molecular structure of the collagen fibril and how it affects collagen proteolysis or "collagenolysis." The fibril-forming collagens are major components of all mammalian connective tissues, providing the structural and organizational framework for skin, blood vessels, bone, tendon, and other tissues. The triple helix of the collagen molecule is resistant to most proteinases, and the matrix metalloproteinases that do proteolyze collagen are affected by the architecture of collagen fibrils, which are notably more resistant to collagenolysis than lone collagen monomers. Until now, there has been no molecular explanation for this. Full or limited proteolysis of the collagen fibril is known to be a key process in normal growth, development, repair, and cell differentiation, and in cancerous tumor progression and heart disease. Peptide fragments generated by collagenolysis, and the conformation of exposed sites on the fibril as a result of limited proteolysis, regulate these processes and that of cellular attachment, but it is not known how or why. Using computational and molecular visualization methods, we found that the arrangement of collagen monomers in the fibril (its architecture) protects areas vulnerable to collagenolysis and strictly governs the process. This in turn affects the accessibility of a cell interaction site located near the cleavage region. Our observations suggest that the C-terminal telopeptide must be proteolyzed before collagenase can gain access to the cleavage site. Collagenase then binds to the substrate's "interaction domain," which facilitates the triple-helix unwinding/dissociation function of the enzyme before collagenolysis.

Atomic-level differences between brain parenchymal- and cerebrovascular-seeded Aß fibrils.

Alzheimer's disease is characterized by neuritic plaques, the main protein components of which are ß-amyloid (Aß) peptides deposited as ß-sheet-rich amyloid fibrils. Cerebral Amyloid Angiopathy (CAA) consists of cerebrovascular deposits of Aß peptides; it usually accompanies Alzheimer's disease, though it sometimes occurs in the absence of neuritic plaques, as AD also occurs without accompanying CAA. Although neuritic plaques and vascular deposits have similar protein compositions, one of the characteristic features of amyloids is polymorphism, i.e., the ability of a single pure peptide to adopt multiple conformations in fibrils, depending on fibrillization conditions. For this reason, we asked whether the Aß fibrils in neuritic plaques differed structurally from those in cerebral blood vessels. To address this question, we used seeding techniques, starting with amyloid-enriched material from either brain parenchyma or cerebral blood vessels (using meninges as the source). These amyloid-enriched preparations were then added to fresh, disaggregated solutions of Aß to make replicate fibrils, as described elsewhere. Such fibrils were then studied by solid-state NMR, fiber X-ray diffraction, and other biophysical techniques. We observed chemical shift differences between parenchymal vs. vascular-seeded replicate fibrils in select sites (in particular, Ala2, Phe4, Val12, and Gln15 side chains) in two-dimensional 13C-13C correlation solid-state NMR spectra, strongly indicating structural differences at these sites. X-ray diffraction studies also indicated that vascular-seeded fibrils displayed greater order than parenchyma-seeded fibrils in the "side-chain dimension" (~ 10 Å reflection), though the "hydrogen-bond dimensions" (~ 5 Å reflection) were alike. These results indicate that the different nucleation conditions at two sites in the brain, parenchyma and blood vessels, affect the fibril products that get formed at each site, possibly leading to distinct pathophysiological outcomes.

Collagen Structure-Function Mapping Informs Applications for Regenerative Medicine.

Type I collagen, the predominant protein of vertebrates, assembles into fibrils that orchestrate the form and function of bone, tendon, skin, and other tissues. Collagen plays roles in hemostasis, wound healing, angiogenesis, and biomineralization, and its dysfunction contributes to fibrosis, atherosclerosis, cancer metastasis, and brittle bone disease. To elucidate the type I collagen structure-function relationship, we constructed a type I collagen fibril interactome, including its functional sites and disease-associated mutations. When projected onto an X-ray diffraction model of the native collagen microfibril, data revealed a matrix interaction domain that assumes structural roles including collagen assembly, crosslinking, proteoglycan (PG) binding, and mineralization, and the cell interaction domain supporting dynamic aspects of collagen biology such as hemostasis, tissue remodeling, and cell adhesion. Our type III collagen interactome corroborates this model. We propose that in quiescent tissues, the fibril projects a structural face; however, tissue injury releases blood into the collagenous stroma, triggering exposure of the fibrils' cell and ligand binding sites crucial for tissue remodeling and regeneration. Applications of our research include discovery of anti-fibrotic antibodies and elucidating their interactions with collagen, and using insights from our angiogenesis studies and collagen structure-function model to inform the design of super-angiogenic collagens and collagen mimetics.

Intermolecular channels direct crystal orientation in mineralized collagen.

The mineralized collagen fibril is the basic building block of bone, and is commonly pictured as a parallel array of ultrathin carbonated hydroxyapatite (HAp) platelets distributed throughout the collagen. This orientation is often attributed to an epitaxial relationship between the HAp and collagen molecules inside 2D voids within the fibril. Although recent studies have questioned this model, the structural relationship between the collagen matrix and HAp, and the mechanisms by which collagen directs mineralization remain unclear. Here, we use XRD to reveal that the voids in the collagen are in fact cylindrical pores with diameters of ~2 nm, while electron microscopy shows that the HAp crystals in bone are only uniaxially oriented with respect to the collagen. From in vitro mineralization studies with HAp, CaCO3 and γ-FeOOH we conclude that confinement within these pores, together with the anisotropic growth of HAp, dictates the orientation of HAp crystals within the collagen fibril.

Evidence for novel beta-sheet structures in Iowa mutant beta-amyloid fibrils.

Asp23-to-Asn mutation within the coding sequence of beta-amyloid, called the Iowa mutation, is associated with early onset, familial Alzheimer's disease and cerebral amyloid angiopathy, in which patients develop neuritic plaques and massive vascular deposition predominantly of the mutant peptide. We examined the mutant peptide, D23N-Abeta40, by electron microscopy, X-ray diffraction, and solid-state NMR spectroscopy. D23N-Abeta40 forms fibrils considerably faster than the wild-type peptide (k = 3.77 x 10(-3) min(-1) and 1.07 x 10(-4) min(-1) for D23N-Abeta40 and the wild-type peptide WT-Abeta40, respectively) and without a lag phase. Electron microscopy shows that D23N-Abeta40 forms fibrils with multiple morphologies. X-ray fiber diffraction shows a cross-beta pattern, with a sharp reflection at 4.7 A and a broad reflection at 9.4 A, which is notably smaller than the value for WT-Abeta40 fibrils (10.4 A). Solid-state NMR measurements indicate molecular level polymorphism of the fibrils, with only a minority of D23N-Abeta40 fibrils containing the in-register, parallel beta-sheet structure commonly found in WT-Abeta40 fibrils and most other amyloid fibrils. Antiparallel beta-sheet structures in the majority of fibrils are indicated by measurements of intermolecular distances through (13)C-(13)C and (15)N-(13)C dipole-dipole couplings. An intriguing possibility exists that there is a relationship between the aberrant structure of D23N-Abeta40 fibrils and the unusual vasculotropic clinical picture in these patients.

A structural prospective for collagen receptors such as DDR and their binding of the collagen fibril.

The structure of the collagen fibril surface directly effects and possibly assists the management of collagen receptor interactions. An important class of collagen receptors, the receptor tyrosine kinases of the Discoidin Domain Receptor family (DDR1 and DDR2), are differentially activated by specific collagen types and play important roles in cell adhesion, migration, proliferation, and matrix remodeling. This review discusses their structure and function as it pertains directly to the fibrillar collagen structure with which they interact far more readily than they do with isolated molecular collagen. This prospective provides further insight into the mechanisms of activation and rational cellular control of this important class of receptors while also providing a comparison of DDR-collagen interactions with other receptors such as integrin and GPVI. When improperly regulated, DDR activation can lead to abnormal cellular proliferation activities such as in cancer. Hence how and when the DDRs associate with the major basis of mammalian tissue infrastructure, fibrillar collagen, should be of keen interest.