No abstract

Protein structures are valuable tools to understand protein function. Nonetheless, proteins are often considered as rigid macromolecules while their structures exhibit specific flexibility, which is essential to complete their functions. Analyses of protein structures and dynamics are often performed with a simplified three-state description, i.e., the classical secondary structures. More precise and complete description of protein backbone conformation can be obtained using libraries of small protein fragments that are able to approximate every part of protein structures. These libraries, called structural alphabets (SAs), have been widely used in structure analysis field, from definition of ligand binding sites to superimposition of protein structures. SAs are also well suited to analyze the dynamics of protein structures. Here, we review innovative approaches that investigate protein flexibility based on SAs description. Coupled to various sources of experimental data (e.g., B-factor) and computational methodology (e.g., Molecular Dynamic simulation), SAs turn out to be powerful tools to analyze protein dynamics, e.g., to examine allosteric mechanisms in large set of structures in complexes, to identify order/disorder transition. SAs were also shown to be quite efficient to predict protein flexibility from amino-acid sequence. Finally, in this review, we exemplify the interest of SAs for studying flexibility with different cases of proteins implicated in pathologies and diseases.

Factor VIII-von Willebrand factor (FVIII⅐vWF) complex, a molecule involved in coagulation, can be physically associated with osteoprotegerin (OPG). OPG is an anti-osteoclastic protein and a soluble receptor for the proapoptotic protein TRAIL (tumor necrosis factor-related apoptosis-inducing ligand), suggesting a potential role of FVIII⅐vWF complex in bone and cancer biology. We, thus, assessed the effects of FVIII⅐vWF complex on osteoclastogenesis and cell survival. We first evidenced that FVIII⅐vWF complex inhibited RANKL-induced osteoclastogenesis and enhanced the inhibitory effect of OPG. Interestingly, we revealed by surface plasmon resonance that FVIII⅐vWF complex bound to RANKL, whereas recombinant FVIII and vWF did not. By modeling, we showed that the OPG binding domain to the A1 domain of vWF was closely located and partially overlapped to its binding site to RANKL. Then, we demonstrated that FVIII⅐vWF complex cancelled the inhibitory activity of OPG on TRAIL-induced apoptosis and characterized interactions between these molecules. The present work evidenced a direct activity of FVIII⅐vWF complex on osteoclasts and on induced cell apoptosis, pointing out its potential involvement in physiological bone remodeling or in bone damages associated with severe hemophilia and cancer development.The molecular triad osteoprotegerin (OPG) 3 /RANK/RANKL is a crucial parameter of bone biology. Receptor activator of nuclear factor B ligand (RANKL), a member of the tumor necrosis factor family, is mainly expressed by osteoblasts in the bone microenvironment and acts as a pro-resorption factor (1, 2); RANKL binds to its receptor RANK expressed at the cell surface of osteoclast precursors and induces osteoclastic differentiation and maturation, leading to bone resorption (3, 4). OPG, also mainly produced by osteoblasts, is a soluble decoy receptor for RANKL, preventing the binding of RANKL to RANK and, thus, inhibiting osteoclastogenesis (5-7). Bone turnover is tightly controlled by the OPG/RANK/RANKL triad, and any change in the balance OPG/RANKL leads to pathological conditions (7). OPG is also a receptor for tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) (8, 9), a cytokine that is able to induce a rapid cancer cell death by apoptosis (9 -11). Interestingly, the binding of OPG to TRAIL completely inhibits TRAIL-induced cytotoxicity (8). OPG possesses antiapoptotic properties and, therefore, could be considered as a pro-tumoral agent.Factor VIII is a plasma glycoprotein mainly synthesized by hepatocytes but also by kidney, sinusoidal endothelial cells, and in small amounts by lymphatic tissues (12). Factor VIII is one of the main coagulation factors and allows the completion of the coagulation process. Factor VIII circulates in plasma in a noncovalent complex with the von Willebrand factor (FVIII⅐vWF complex). The most well known genetic disease associated with Factor VIII is hemophilia A, which shows an X-linked inheritance (13). A second important disease associated with low Factor VIII levels is von ...