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

Perumal, Shiamalee; Antipova, Olga; Orgel, Joseph P. R. O.

doi:10.1073/pnas.0710588105

Cited by 310 publications

(343 citation statements)

References 36 publications

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“…Indeed, important experimental crystallography [57,58] efforts are ongoing to elucidate the structure of collagen fibril-proteoglycan complexes. Other challenges remain with respect to the greater level of disorder that is expected to be found in collagen fibrils, as outlined in [59]. Our model represents a collagen "microfibril", whereas larger-scale collagen fibrils may feature additional interfaces and disorder between them that could affect the mechanical properties.…”

Section: Resultsmentioning

confidence: 99%

“…For example, even though the mechanical analysis of the modulus of dehydrated (dry) collagen microfibril agrees well with experimental findings (with similar Young's modulus values as shown in Table 1), the Ramachandran analysis suggest a heightened level of disorder in the system, perhaps indicative of molecular unfolding. Drastic changes in the molecular architecture associated with such mechanisms could be explored via the use of advanced computational methods, such as Replica Exchange Molecular Dynamics and should be combined with experimental efforts such as outlined in [59]. The computational challenges associated with these methods are, however, enormous.…”

Section: Resultsmentioning

confidence: 99%

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Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Gautieri

Vesentini²,

Redaelli³

et al. 2011

Nano Lett.

611

488

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Abstract:Collagen constitutes one third of the human proteome, providing mechanical stability, elasticity and strength to connective tissues. Collagen is also the dominating material in the extracellular matrix (ECM) and is thus crucial for cell differentiation, growth and pathology. However, fundamental questions remain with respect to the origin of the unique mechanical properties of collagenous tissues, and in particular its stiffness, extensibility and nonlinear mechanical response. By using x-ray diffraction data of a collagen fibril reported by Orgel et al.(Proceedings of the National Academy of Sciences USA, 2006) in combination with protein structure identification methods, here we present an experimentally validated model of the nanomechanics of a collagen microfibril that incorporates the full biochemical details of the amino acid sequence of the constituting molecules. We report the analysis of its mechanical properties under different levels of stress and solvent conditions, using a full-atomistic force field including explicit water solvent. Mechanical testing of hydrated collagen microfibrils yields a Young's modulus of ≈300 MPa at small and ≈1.2 GPa at larger deformation in excess of 10% strain, in excellent agreement with experimental data. Dehydrated, dry collagen microfibrils show a significantly increased Young's modulus of ≈1.8 to 2.25 GPa (or ≈6.75 times the modulus in the wet state) owing to a much tighter molecular packing, in good agreement with experimental measurements (where an increase of the modulus by ≈9 times was found). Our model demonstrates that the unique mechanical properties of collagen microfibrils can be explained based on their hierarchical structure, where deformation is mediated through mechanisms that operate at different hierarchical levels. Key mechanisms involve straightening of initially disordered and helically twisted molecules at small strains, followed by axial stretching of molecules, and eventual molecular uncoiling at extreme deformation. These mechanisms explain the striking difference of the modulus of collagen fibrils compared with single molecules, which is found in the range of 4.8±2 GPa or ≈10-20 times greater. These findings corroborate the notion that collagen tissue properties are highly scale dependent and nonlinear elastic, an issue that must be considered in the development of models that describe the interaction of cells with collagen in the extracellular matrix. A key impact the atomistic model of collagen microfibril mechanics reported here is that it enables the bottom-up elucidation of structure-property relationships in the broader class of collagen materials such as tendon or bone, including studies in the context of genetic disease where the incorporation of biochemical, genetic details in material models of connective tissue is essential.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Gautieri

Vesentini²,

Redaelli³

et al. 2011

Nano Lett.

611

488

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“…We believe this result may be interesting in light of preferential ␣ 2 (I) cleavage by MMP-1 (28,35,36) and possible 8 -9 FnI implications on collagenolysis (see below). Singlestranded ␣ 1 (I) peptide binding to GBD is not cooperative.…”

Section: Discussionmentioning

confidence: 99%

“…We infer from the structural data that the core [8][9] FnI-binding site of collagen comprises the peptide ␤-strand GLOGQRGER, which includes an integrin-binding motif (25,26) with moderate affinity for activated cells (27). In addition, this sequence comprises the proposed recognition site (RGER) of MMP-1 that defines the 3/4 region as the site of collagenolysis (28). This sequence is almost identical between the ␣ 1 (I) and ␣ 2 (I) chains, which would explain their similar affinity to [8][9] FnI shown above.…”

Section: -Fam-q 774 -Omentioning

confidence: 99%

Identification and structural analysis of type I collagen sites in complex with fibronectin fragments

Erat¹,

Slatter

Lowe

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

136

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Collagen and fibronectin are major components of vertebrate extracellular matrices. Their association and distribution control the development and properties of diverse tissues, but thus far no structural information has been available for the complex formed. Here, we report binding of a peptide, derived from the ␣1 chain of type I collagen, to the gelatin-binding domain of human fibronectin and present the crystal structure of this peptide in complex with the 8 -9 FnI domain pair. Both gelatin-binding domain subfragments, 6 FnI 1-2 FnII 7 FnI and 8 -9 FnI, bind the same specific sequence on D-period 4 of collagen I ␣1, adjacent to the MMP-1 cleavage site. 8 -9 FnI also binds the equivalent sequence of the ␣2 chain. The collagen peptide adopts an antiparallel ␤-strand conformation, similar to structures of proteins from pathogenic bacteria bound to FnI domains. Analysis of the type I collagen sequence suggests multiple putative fibronectin-binding sites compatible with our structural model. We demonstrate, by kinetic unfolding experiments, that the triple-helical collagen state is destabilized by 8 -9 FnI. This finding suggests a role for fibronectin in collagen proteolysis and tissue remodeling.collagen destabilization ͉ extracellular matrix ͉ protein structure C ollagen is the most abundant protein in mammals, accounting for Ϸ25% of the body-protein content. It is crucial for effects as diverse as cell differentiation, cell migration, and mechanical properties of tissues. Many human diseases have their origin in mutations that affect interactions of collagen with other extracellular matrix (ECM) molecules and cell receptors (1). Type I collagen fibrils form spontaneously in vitro; in vivo, however, formation requires integrin receptors and fibronectin (FN) (2). FN is a large glycosylated protein composed of multiple copies of 3 classes of domains, FnI, FnII, and FnIII, that forms fibrils in the ECM (3). It plays a role in many important physiological processes, such as embryogenesis, wound healing, hemostasis, and thrombosis (4), and disruption of the FN gene is embryonic lethal in mice (5).The interaction of these 2 proteins has long been demonstrated in vitro by using denatured collagen (gelatin) (6, 7) and isolated collagen type I chains or chain fragments (8, 9). The collagen-binding site on FN has been localized to the 42-kDa gelatin-binding domain (GBD; for an overview of FN and collagen fragments see Fig. 1) (10, 11), and anti-GBD antibodies inhibit collagen organization in fibroblast cultures (12). Similarly, experiments in cultures have identified the collagenase/ MMP-1 (13) cleavage site in type I collagen as important for FN-mediated attachment of fibroblasts to collagen ECM (14). Peptides spanning that region (15) or MMP-1 cleavage at this site (6) inhibit attachment. However, attempts to reconstitute the FN-collagen interaction in vitro by using synthetic peptides failed to find strong, specific, interactions (8,9), and the precise sequence determinants for FN-binding to collagen remained unknown...

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“…The triple-helical structure of COL1 is resistant to almost all forms of proteolytic cleavage (BirkedalHansen, 1987;Perumal et al, 2008). To date, type I collagenolytic activity is confined to a small subset of proteinases belonging to either the cysteine proteinase or matrix metalloproteinase (MMP) families (BirkedalHansen, 1987;Nagase et al, 2006;Sabeh et al, 2009a).…”

Section: Introductionmentioning

confidence: 99%

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

et al. 2011

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As invading breast carcinoma cells breach their underlying basement membrane, they become confronted with a dense three-dimensional reactive stroma dominated by type I collagen. To develop metastatic capabilities, invading tumor cells must acquire the capacity to negotiate this novel microenvironment. Collagen influences the fate of epithelial cells by inducing apoptosis. However, the mechanisms used by invading tumor cells to evade collagen-induced apoptosis remain to be defined. We demonstrate that membrane type-1 matrix metalloproteinase (MT1-MMP/MMP-14) confers breast cancer cells with the ability to escape apoptosis when embedded in a collagen gel and after orthotopic implantation in vivo. In the absence of MMP-14-dependent proteolysis, type I collagen triggers apoptosis by inducing the expression of the pro-apoptotic Bcl-2-interacting killer in luminallike breast cancer cells. These findings reveal a new mechanism whereby MMP-14 activity promotes tumor progression by circumventing apoptosis.

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

Cited by 310 publications

References 36 publications

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Hierarchical Structure and Nanomechanics of Collagen Microfibrils from the Atomistic Scale Up

Identification and structural analysis of type I collagen sites in complex with fibronectin fragments

MT1-MMP protects breast carcinoma cells against type I collagen-induced apoptosis

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