scholarly journals Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

Cells ◽  
2020 ◽  
Vol 9 (3) ◽  
pp. 610 ◽  
Author(s):  
Peter G. Chandler ◽  
Ashley M. Buckle
Keyword(s):  
Clinical Stage ◽  
Natural Function ◽  
Disulphide Bonds ◽  
Fibronectin Type Iii ◽  
Development And Differentiation ◽  
Multiple Conformations ◽  
Type 3 ◽  
Fn3 Domain ◽  
Fibronectin Assembly ◽  
Fibronectin Type

As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for the design of new therapeutics. In response, clinical-stage therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing between chains, multiple FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.

scholarly journals Development and Differentiation in Monobodies Based on the Fibronectin Type 3 Domain

2020 ◽  
Author(s):  
Peter G. Chandler ◽  
Ashley M. Buckle
Keyword(s):  
Simple Structure ◽  
Natural Function ◽  
Disulphide Bonds ◽  
Fibronectin Type Iii ◽  
Development And Differentiation ◽  
Multiple Conformations ◽  
Type 3 ◽  
Fn3 Domain ◽  
Fibronectin Assembly ◽  
Fibronectin Type

As a non-antibody scaffold, monobodies based on the fibronectin type III (FN3) domain overcome antibody size and complexity while maintaining analogous binding loops. However, antibodies and their derivatives remain the gold standard for design of new therapeutics. In response, clinical therapeutic proteins based on the FN3 domain are beginning to use native fibronectin function as a point of differentiation. The small and simple structure of monomeric monobodies confers increased tissue distribution and reduced half-life, whilst the absence of disulphide bonds improves stability in cytosolic environments. Where multi-specificity is challenging with an antibody format that is prone to mis-pairing of chains, FN3 domains in the fibronectin assembly already interact with a large number of molecules. As such, multiple monobodies engineered for interaction with therapeutic targets are being combined in a similar beads-on-a-string assembly which improves both efficacy and pharmacokinetics. Furthermore, full length fibronectin is able to fold into multiple conformations as part of its natural function and a greater understanding of how mechanical forces allow for the transition between states will lead to advanced applications that truly differentiate the FN3 domain as a therapeutic scaffold.

scholarly journals Crystal structure of the second fibronectin type III (FN3) domain from human collagen α1 type XX

2017 ◽  
Vol 73 (12) ◽  
pp. 695-700 ◽  
Author(s):  
Jingfeng Zhao ◽  
Jixia Ren ◽  
Nan Wang ◽  
Zhong Cheng ◽  
Runmei Yang ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Structural Similarity ◽  
Type Iii ◽  
Nmr Structures ◽  
Fibronectin Type Iii ◽  
Human Collagen ◽  
And Function ◽  
Fn3 Domain ◽  
Β Sheet ◽  
Fibronectin Type

Collagen α1 type XX, which contains fibronectin type III (FN3) repeats involving six FN3 domains (referred to as the FN#1–FN#6 domains), is an unusual member of the fibril-associated collagens with interrupted triple helices (FACIT) subfamily of collagens. The results of standard protein BLAST suggest that the FN3 repeats might contribute to collagen α1 type XX acting as a cytokine receptor. To date, solution NMR structures of the FN#3, FN#4 and FN#6 domains have been determined. To obtain further structural evidence to understand the relationship between the structure and function of the FN3 repeats from collagen α1 type XX, the crystal structure of the FN#2 domain from human collagen α1 type XX (residues Pro386–Pro466; referred to as FN2-HCXX) was solved at 2.5 Å resolution. The crystal structure of FN2-HCXX shows an immunoglobulin-like fold containing a β-sandwich structure, which is formed by a three-stranded β-sheet (β1, β2 and β5) packed onto a four-stranded β-sheet (β3, β4, β6 and β7). Two consensus domains, tencon and fibcon, are structural analogues of FN2-HCXX. Fn8, an FN3 domain from human oncofoetal fibronectin, is the closest structural analogue of FN2-HCXX derived from a naturally occurring sequence. Based solely on the structural similarity of FN2-HCXX to other FN3 domains, the detailed functions of FN2-HCXX and the FN3 repeats in collagen α1 type XX cannot be identified.

scholarly journals Administration of Bifidobacterium breve Improves the Brain Function of Aβ1-42-Treated Mice via the Modulation of the Gut Microbiome

Nutrients ◽  
2021 ◽  
Vol 13 (5) ◽  
pp. 1602
Author(s):  
Guangsu Zhu ◽  
Jianxin Zhao ◽  
Hao Zhang ◽  
Wei Chen ◽  
Gang Wang
Keyword(s):  
Gut Microbiome ◽  
Dietary Intervention ◽  
Neuroprotective Effects ◽  
Bifidobacterium Breve ◽  
Beneficial Effects ◽  
Behavioral Abnormalities ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
The Brain ◽  
Fibronectin Type

Psychobiotics are used to treat neurological disorders, including mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the mechanisms underlying their neuroprotective effects remain unclear. Herein, we report that the administration of bifidobacteria in an AD mouse model improved behavioral abnormalities and modulated gut dysbiosis. Bifidobacterium breve CCFM1025 and WX treatment significantly improved synaptic plasticity and increased the concentrations of brain-derived neurotrophic factor (BDNF), fibronectin type III domain-containing protein 5 (FNDC5), and postsynaptic density protein 95 (PSD-95). Furthermore, the microbiome and metabolomic profiles of mice indicate that specific bacterial taxa and their metabolites correlate with AD-associated behaviors, suggesting that the gut–brain axis contributes to the pathophysiology of AD. Overall, these findings reveal that B. breve CCFM1025 and WX have beneficial effects on cognition via the modulation of the gut microbiome, and thus represent a novel probiotic dietary intervention for delaying the progression of AD.

scholarly journals A targeted adenovirus vector displaying a human fibronectin type III domain-based monobody in a fiber protein

Biomaterials ◽  
2013 ◽  
Vol 34 (16) ◽  
pp. 4191-4201 ◽  
Author(s):  
Hayato Matsui ◽  
Fuminori Sakurai ◽  
Kazufumi Katayama ◽  
Yasuhiro Abe ◽  
Mitsuhiro Machitani ◽  
...  
Keyword(s):  
Adenovirus Vector ◽  
Type Iii ◽  
Fiber Protein ◽  
Fibronectin Type Iii ◽  
Human Fibronectin ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

scholarly journals Tuning the Mechanical Stability of Fibronectin Type III Modules through Sequence Variations

Structure ◽  
2004 ◽  
Vol 12 (1) ◽  
pp. 21-30 ◽  
Author(s):  
David Craig ◽  
Mu Gao ◽  
Klaus Schulten ◽  
Viola Vogel
Keyword(s):  
Mechanical Stability ◽  
Type Iii ◽  
Sequence Variations ◽  
Fibronectin Type Iii ◽  
Fibronectin Type

scholarly journals Structural Studies of an Immunoglobulin-Fibronectin Type III Domain Tandem from Titin

2011 ◽  
Vol 100 (3) ◽  
pp. 604a
Author(s):  
Andras Czajlik ◽  
Gary Thompson ◽  
Ghulam N. Khan ◽  
Arnout Kalverde ◽  
Steve W. Homans ◽  
...  
Keyword(s):  
Structural Studies ◽  
Type Iii ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Novel tenascin variants with a distinctive pattern of expression in the avian embryo

Development ◽  
1994 ◽  
Vol 120 (3) ◽  
pp. 637-647
Author(s):  
R.P. Tucker ◽  
J. Spring ◽  
S. Baumgartner ◽  
D. Martin ◽  
C. Hagios ◽  
...  
Keyword(s):  
Genomic Library ◽  
Chicken Embryo Fibroblast ◽  
Cdna Probe ◽  
Avian Embryo ◽  
Degenerate Primers ◽  
Type Iii ◽  
Embryonic Tissues ◽  
Fibronectin Type Iii ◽  
Fibronectin Type

Previous studies have shown that several forms of the glycoprotein tenascin are present in the embryonic extracellular matrix. These forms are the result of alternative splicing, which generates tenascin variants with different numbers of fibronectin type III repeats. We have used degenerate primers and PCR to isolate a novel tenascin exon from an avian genomic library. Genomic clones contained a sequence encoding a fibronectin type III repeat that corresponds to repeat ‘C’ from the variable domain of human tenascin. To demonstrate that tenascin containing repeat ‘C’ is actually synthesized by avian cells, a monospecific antiserum was raised against a repeat ‘C’ fusion protein. This antiserum recognized a novel high-molecular-weight variant on immunoblots of tenascin isolated from chicken embryo fibroblast-conditioned medium, and stained tendons on frozen sections of chicken embryos. A cDNA probe specific for mRNA encoding repeat ‘C’ was used for in situ hybridization. This probe hybridized in a subset of the embryonic tissues labelled with a universal tenascin probe, including tendons, ligaments and mesenchyme at sites of epithelial-mesenchymal interactions. Finally, we provide evidence that additional fibronectin type III repeats, one corresponding to a recently discovered human repeat as well as one entirely novel sequence, also exists in chicken tenascin mRNA. These data indicate that tenascin is present in the embryonic matrix in a multitude of forms and that these forms have distinctive distributions that may reflect more than one function for tenascin in development.

scholarly journals Interaction of CREB and PGC-1α Induces Fibronectin Type III Domain-Containing Protein 5 Expression in C2C12 Myotubes

2018 ◽  
Vol 50 (4) ◽  
pp. 1574-1584 ◽  
Author(s):  
Xiu-ying Yang ◽  
Margaret C.L. Tse ◽  
Xiang Hu ◽  
Wei-hua Jia ◽  
Guan-hua Du ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Molecular Mechanisms ◽  
Metabolic Effects ◽  
Hek293 Cells ◽  
Metabolic Phenotype ◽  
C2c12 Myotubes ◽  
Type Iii ◽  
Fibronectin Type Iii ◽  
Fibronectin Type Iii Domain ◽  
Fibronectin Type

Background/Aims: Fibronectin type III domain-containing protein 5 (FNDC5), also known as irisin, is a myokine secreted from muscle in response to exercise. However, the molecular mechanisms that regulate FNDC5 expression and the functional significance of irisn in skeletal muscle remain unknown. In this study, we explored the potential pathways that induce FNDC5 expression and delineated the metabolic effects of irisin on skeletal muscle. Methods: C2C12 myotubes were treated with drugs at various concentrations and durations. The expression and activation of genes were measured by real-time polymerase chain reaction (qRT-PCR) and Western blotting. Oxidative phosphorylation was quantified by measuring the oxygen consumption rate (OCR). Results: We found that the exercise-mimicking treatment (cAMP, forskolin and isoproterenol) increased Fndc5 expression in C2C12 myotubes. CREB over-expressed C2C12 myotubes displayed higher Fndc5 expression. CREB over-expression also promoted peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α) expression. PGC-1α-induced Fndc5 expression was blocked when the dominant negative form of CREB (S133A) was present. PGC-1α mutation (S570A) also decreased Fndc5 expression. Immunoprecipitation showed that overexpressed PGC-1α complexed with CREB in HEK293 cells. C2C12 myotubes treated with forskolin also increased endogenous CREB and PGC-1α binding. Functionally, irisin treatment increased mitochondrial respiration, enhanced ATP production, promoted fatty acid oxidation but decreased glycolysis in myotubes. Conclusion: Our observation indicates that cAMP-mediated PGC-1α/CREB interaction triggers Fndc5 expression, which acts as an autocrine/paracrine to shape the metabolic phenotype of myotubes.

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