The development of SERI® Surgical Scaffold, an engineered biological scaffold
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The primary goal of reconstructive and revision surgery is to restore, repair, rebuild, and support damaged, weakened, or absent tissue. There are numerous approaches for soft tissue support and repair, including the use of autologous tissue, human‐ or animal‐derived acellular dermal matrices, absorbable or permanent synthetic mesh, and, now, a new class of bioresorbable protein scaffold. Although many factors influence the choice of surgical approach and the specific product used for soft tissue support and repair, the goal is to improve long‐term outcomes while minimizing complications and recurrences requiring further revisional surgery. In this review, the basic science, clinical characteristics, and clinical applications of SERI ® Surgical Scaffold, a novel, engineered, highly purified silk product for soft tissue support and repair will be presented.Cooperativity
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Abstract Chromosome higher order structure has been an enigma for over a century. The most important structural finding has been the presence of a chromosome scaffold composed of non-histone proteins; so-called scaffold proteins. However, the organization and function of the scaffold are still controversial. Here, we use three dimensional-structured illumination microscopy (3D-SIM) and focused ion beam/scanning electron microscopy (FIB/SEM) to reveal the axial distributions of scaffold proteins in metaphase chromosomes comprising two strands. We also find that scaffold protein can adaptably recover its original localization after chromosome reversion in the presence of cations. This reversion to the original morphology underscores the role of the scaffold for intrinsic structural integrity of chromosomes. We therefore propose a new structural model of the chromosome scaffold that includes twisted double strands, consistent with the physical properties of chromosomal bending flexibility and rigidity. Our model provides new insights into chromosome higher order structure.
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Scaffold proteins regulate cell signalling by promoting the proximity of putative interaction partners. Although they are frequently applied in cellular settings, fundamental understanding of them in terms of, amongst other factors, quantitative parameters has been lagging behind. Here we present a scaffold protein platform that is based on the native 14-3-3 dimeric protein and is controllable through the action of a small-molecule compound, thus permitting study in an in vitro setting and mathematical description. Robust small-molecule regulation of caspase-9 activity through induced dimerisation on the 14-3-3 scaffold was demonstrated. The individual parameters of this system were precisely determined and used to develop a mathematical model of the scaffolding concept. This model was used to elucidate the strong cooperativity of the enzyme activation mediated by the 14-3-3 scaffold. This work provides an entry point for the long-needed quantitative insights into scaffold protein functioning and paves the way for the optimal use of reengineered 14-3-3 proteins as chemically inducible scaffolds in synthetic systems.
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Motivation: Scaffold proteins are known as crucial regulators of various cellular functions by assembling multiple proteins involved in signaling and metabolic pathways. Identification of scaffold proteins and the study of their molecular mechanisms can open a new aspect of cellular systemic regulation and the resulting application on medicine and engineering. There have been highlighted the regulatory roles of dozens of scaffold proteins, but just one computational approach tried to find scaffold proteins from interactomes until now. However, there was a limitation to find diverse types of scaffold proteins because their criteria were restricted to the classical scaffold proteins.
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Scaffold proteins operate as organizing hubs to enable high-fidelity signaling, fulfilling crucial roles in the regulation of cellular processes. Bottom-up construction of controllable scaffolding platforms is attractive for the implementation of regulatory processes in synthetic biology. Here, we present a modular and switchable synthetic scaffolding system, integrating scaffold-mediated signaling with switchable kinase/phosphatase input control. Phosphorylation-responsive inhibitory peptide motifs were fused to 14-3-3 proteins to generate dimeric protein scaffolds with appended regulatory peptide motifs. The availability of the scaffold for intermolecular partner protein binding could be lowered up to 35-fold upon phosphorylation of the autoinhibition motifs, as demonstrated using three different kinases. In addition, a hetero-bivalent autoinhibitory platform design allowed for dual-kinase input regulation of scaffold activity. Reversibility of the regulatory platform was illustrated through phosphatase-controlled abrogation of autoinhibition, resulting in full recovery of 14-3-3 scaffold activity.
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Scaffold proteins play an important role in coordinating signal transduction cascades. However, their exact mechanism of action and the ultimate effect they have on the signal output remain unclear. Ferrell discusses how computer simulations have provided insight into the multiple possible functions that scaffold proteins may have. What remains is to test the predictions in real cells to determine what difference the presence of a scaffold really makes in the output of a signaling pathway.
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Scaffold proteins are known for being crucial regulators of various cellular functions by assembling multiple proteins involved in signaling and metabolic pathways. Identification of scaffold proteins and the study of their molecular mechanisms can open a new aspect of cellular systemic regulation and the results can be applied in the field of medicine and engineering. Despite being highlighted as the regulatory roles of dozens of scaffold proteins, there was only one known computational approach carried out so far to find scaffold proteins from interactomes. However, there were limitations in finding diverse types of scaffold proteins because their criteria were restricted to the classical scaffold proteins. In this paper, we will suggest a systematic approach to predict massive scaffold proteins from interactomes and to characterize the roles of scaffold proteins comprehensively.From a total of 10,419 basic scaffold protein candidates in protein interactomes, we classified them into three classes according to the structural evidences for scaffolding, such as domain architectures, domain interactions and protein complexes. Finally, we could define 2716 highly reliable scaffold protein candidates and their characterized functional features. To assess the accuracy of our prediction, the gold standard positive and negative data sets were constructed. We prepared 158 gold standard positive data and 844 gold standard negative data based on the functional information from Gene Ontology consortium. The precision, sensitivity and specificity of our testing was 80.3, 51.0, and 98.5 % respectively. Through the function enrichment analysis of highly reliable scaffold proteins, we could confirm the significantly enriched functions that are related to scaffold protein binding. We also identified functional association between scaffold proteins and their recruited proteins. Furthermore, we checked that the disease association of scaffold proteins is higher than kinases.In conclusion, we could predict larger volume of scaffold proteins and analyzed their functional characteristics. Deeper understandings about the roles of scaffold proteins from this study will provide a higher opportunity to find therapeutic or engineering applications of scaffold proteins using their functional characteristics.
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Assembly of proteins into higher-order complexes generates specificity and selectivity in cellular signaling. Signaling complex formation is facilitated by scaffold proteins that use modular scaffolding domains, which recruit specific pathway enzymes. Multimerization and recombination of these conjugated native domains allows the generation of libraries of engineered multidomain scaffold proteins. Analysis of these engineered proteins has provided molecular insight into the regulatory mechanism of the native scaffold proteins and the applicability of these synthetic variants. This topical review highlights the use of engineered, conjugated multidomain scaffold proteins on different length scales in the context of synthetic signaling pathways, metabolic engineering, liquid–liquid phase separation, and hydrogel formation.
Protein Engineering
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Scaffold proteins play an important role in coordinating signal transduction cascades. However, their exact mechanism of action and the ultimate effect they have on the signal output remain unclear. Ferrell discusses how computer simulations have provided insight into the multiple possible functions that scaffold proteins may have. What remains is to test the predictions in real cells to determine what difference the presence of a scaffold really makes in the output of a signaling pathway.
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The synthesis of a new triazacyclophane scaffold (TACO scaffold) containing three selectively deprotectable amines is described. The TACO scaffold is conformationally more constrained than our frequently used TAC scaffold, due to introduction of a substituent on the para position of the benzoic acid hinge, which prevents ring flipping and makes it more attractive than the TAC scaffold for preparation of artificial receptor molecules or for mimicking discontinuous epitopes toward protein mimics when more preorganization is required.
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