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SH3 domain in Bin1 protein
Introduction
The SH3, or Src homology 3 domain is a region of the Bin1 protein, also known as Bridging Integrator 1 protein. This domain represents a very important part for protein-protein interactions inside the cell. This domain is known for its ability to recognize and bind to proline-rich sequences of proteins and also mediate the assembly of protein complexes. Bin1 is involved in many cellular processes such as cytoskeleton regulation, membrane dynamics and cell signaling, and employs its SH3 domain tin the aim of interact with specific partners and modulates key biological pathways, notably those involved in cancer and neurodegenerative diseases.
‘’’1. Structure of the SH3 site of Protein Bin1’’’
‘’’1.1 Amino acid composition’’’
The SH3 site of the Bin1 protein is a highly conserved polypeptide sequence. It consists of around 50 to 60 amino acids. This region is characterized by a specific amino acid composition, including proline residues, hydrophobic residues and charged residues, which are involved in the formation of the three-dimensional structure and stabilization of the SH3 domain.
‘’’1.2 Three-dimensional structure’’’
The three-dimensional structure of the SH3 site of the Bin1 protein has been determined by techniques such as X-ray crystallography and NMR. This region presents a globular barrel-shaped conformation that is characterized by five to six antiparallel β-strands and a few short α-helices, and this barrel shape presents a peptide-specific binding cavity. It enables recognition and binding of proline-rich binding motifs present in partner proteins with Bin1.
‘’’1.3 Composition of β-strands and α-helices’’’
Hydrogen bonds between the oxygen and nitrogen atoms of the amino acid residues stabilize the β-strands of Bin1's SH3. It promotes the formation of an antiparallel β-sheet. The α-helices, although they are less abundant, also contribute to the globular structure of the SH3 domain by providing additional conformational flexibility.
‘’’1.4 Binding cavity’’’
The binding cavity of the SH3 site of the Bin1 protein is formed from specific residues located at the interface of the β-strands and α-helices. This cavity is complementary in shape to the proline-rich binding motifs of the partner proteins, enabling specific recognition and binding. The Interactions between Bin1's SH3 binding cavity and partner peptides have been characterized by molecular modeling studies.
2. Functions of the SH3 site of the Bin1 protein
‘’’2.1 Recognition and binding to Proline-Rich Binding Motifs’’’
In the Bin1 proteins, the SH3 site plays a crucial role in the recognition and specific binding of the proline-rich binding motifs of its protein partners. This interaction is based on complementarity of shape between the binding cavity of the SH3 site and the proline-rich motifs of the protein ligands. The identification of the residues involved in this interaction through site-directed mutagenesis and molecular modeling studies provides a better understanding of the specificity and binding strength of the Bin1 SH3 site.
‘’’2.2 Regulation of Cell Signaling’’’
The interactions of the SH3 site of the Bin1 protein with its protein ligands are essential for the regulation of various cell signalling processes. By acting as a protein-protein binding module, the SH3 site facilitates the formation of functional protein complexes involved in the transmission and amplification of cellular signals. These complexes can regulate several signaling pathways, such as growth factor receptor, G protein-coupled receptor and intracellular signaling pathways.
‘’’2.3 Involvement in Cellular Adhesion’’’
The SH3 site plays a crucial role in the process of regulating cell adhesion by promoting the assembly of complex protein complexes responsible for the construction and consolidation of cell junctions. This protein-protein interaction plays a key role in the dynamics of cell adhesion, conditioning cell migration, differentiation and proliferation. It has been shown that the Bin1 protein is involved in the interaction of cadherins or integrins, which are essential for the formation of cell junctions. Deletion of the SH3 site would have a direct impact on the regulation of cell architecture.
‘’’2.4 Contribution to Cellular Morphology’’’
Finally, the SH3 site of the Bin1 protein also contributes to the regulation of cell morphology by modulating cytoskeletal organization and membrane domain dynamics. Indeed, interactions of the SH3 site with cytoskeletal proteins such as actin and tubulin influence the formation and stabilization of cellular structures such as filopodia, lamellipodia and microvilli. These protein-protein interactions contribute to cell morphogenesis and cellular adaptation to extracellular stimuli.
‘’’3. Mechanisms of action of the SH3 site of the Bin1 protein’’’
‘’’3.1 Non-covalent interactions’’’
The binding mechanism of the Bin1 SH3 site relies mainly on non-covalent interactions, including hydrophobic bonds, electrostatic bonds and steric interactions. The latter enable recognition and binding between the SH3 site and the specific proline-rich binding motifs of partner proteins. Hydrophobic bonds result from hydrophobic particles associating with each other within the binding cavity, while electrostatic bonds involve interactions between charged residues. Steric interactions are due to physical contacts between the atoms of amino acid residues, contributing to the specificity and stability of the bond.
‘’’3.2 Anchoring Proline-Rich Linking Patterns’’’
The shape of the binding cavity of SH3 site is perfect for anchoring the proline-rich binding motifs present in partner proteins, as the cavity is complementary in conformation to these motifs, enabling specific molecular recognition. Thus,molecular modeling studies have also revealed specific interactions between the amino acid residues of the SH3 site and the proline-rich residues of the partner proteins. This interaction contributes to the specificity and binding strength of the protein-protein complex formed.
‘’’3.3 Regulation of subcellular localization’’’
The localization of proteins involved in specific cellular processes are regulated by interactions established by Bin1's SH3 site with its protein partners. In fact, the SH3 site interacts with membrane proteins involved in cell signalling and cytoskeletal dynamics, thereby regulating their recruitment and localization to specific sites in the cell. This spatial regulation is therefore essential for the coordination of cellular processes and the response to extracellular stimuli.
‘’’3.4 Dynamics of multimeric assemblies’’’
The SH3 site of Bin1 is also involved in regulating the dynamics of multimeric assemblies. It thus influences the formation and dissociation of protein complexes. By acting as a protein-protein binding module, the SH3 site promotes the assembly of multimeric complexes involved in cell signalling, cell adhesion regulation and cell morphology. These interactions modulate the stability and dynamics of protein complexes, so the SH3 domain is involved in the fluidity of cellular processes.
‘’’4. Pharmaceutical implications of the SH3 site of the Bin1 protein’’’
‘’’4.1 Potential therapeutic target’’’
Because of its central role in the regulation of cellular processes, the SH3 site of the Bin1 protein represents a promising therapeutic target in the pharmaceutical field. Indeed, modulation of SH3 site interactions would be crucial for the treatment of certain diseases such as cancer and neurodegenerative diseases.
‘’’4.1.1 Cancer’’’
Bin1 protein is involved in the regulation of various cellular processes, such as cell growth and apoptosis, so it plays a role in the development of cancer. In fact, It can act as a potential tumor suppressor by inhibiting tumor growth, and mutations in the SH3 domain can disrupt its function. Also, studies have shown that mutations at the SH3 site are associated with the progression of certain cancers such as breast cancer, where reduced levels of Bin1 have been observed, which may contribute to the growth of metastases. Similarly, in brain cancer, genetic alterations in Bin1 have been observed.
‘’’4.1.2 neurodegenerative diseases’’’
‘’’4.1.2.1 Alzheimer's disease’’’
The Bin1 protein is associated with Alzheimer's disease. In the brains of Alzheimer's patients, Bin1 expression is reduced. The SH3 domain of Bin1 is important because it interacts with the tau protein, which forms the neurofibrillary tangles characteristic of the disease.
‘’’4.1.2.2 ALS’’’
Amyotrophic lateral sclerosis (ALS) is also linked to the SH3 site of Bin1. It is involved in the regulation of vesicular trafficking within the cell and synapse formation, which are impacted in ALS disease. In addition, mutations in the SH3 domain of Bin1 may impair its interaction with other proteins involved in neuronal function, contributing to neurodegeneration.
4.2 Pharmacological strategies
Innovative pharmacological approaches are currently being developed, aimed at specifically disrupting interactions between Bin1's SH3 site and its protein partners. Small molecule inhibitors, peptide mimetics and monoclonal antibodies are potential tools for interfering with the bonds established between SH3 and its partners. This makes it possible to block cellular signalling pathways associated with the pathogenesis of various diseases.
Conclusion
In conclusion, the SH3 site of the Bin1 protein is crucial in the regulation of protein-protein interactions, as well as in the modulation of cellular processes. due to its elaborate three-dimensional structure characterized by a specific binding cavity and molecular recognition motifs. This implies a central role in the coordination of cell signalling pathways. Furthermore, the multifunctionality of the SH3 site, notably its ability to modulate cell adhesion, intracellular signalling and cell morphology, makes it a target of research interest.
The mechanisms of action of the SH3 site are based on a combination of non-covalent interactions and specific molecular recognition. They finely regulate the formation and dynamics of protein complexes, as well as protein localization. This precise regulation of protein-protein interactions is essential for cell physiology. However, it can be disrupted in a variety of pathological conditions.
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2. Mayer, B.J. (1995). SH3 domains: complexity in moderation. Journal of Cell Science, 108(2), 3683-3692.
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4. Prokic, I., et al. (2014). Bridging integrator 1 (BIN1) genotype effects on working memory, hippocampal volume, and functional connectivity in young healthy individuals. Neuropsychopharmacology, 39(9), 2233-2240.
5. Chen, H., et al. (2015). BIN1 Gene rs744373 Polymorphism Contributes to Alzheimer’s Disease in East Asian Population. Journal of Molecular Neuroscience, 55(1), 245-251.
6. Hong, L., et al. (2019). BIN1/M-Amphiphysin2 induces clustering of phosphoinositides to recruit ESCRT-III via its N-BAR domain. Cell Reports, 26(11), 2894-2906.
7. Salzer, U., et al. (2008). BIN1 is a novel MYC-interacting protein with features of a tumour suppressor. Nature Genetics, 40(7), 760-765.
8. Tomlinson, M.G., et al. (2011). SH3 domains of the protein kinase C isoforms α, βII, δ, and ε differentially mediate targeting to F-actin and association with acidic lipids. Journal of Biological Chemistry, 286(7), 8181-8191.
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