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SH2 Domains: Folding, Binding and Therapeutical Approaches
Awa Diop1, Daniele Santorelli1, Francesca Malagrinò1
1Istituto Pasteur-Fondazione Cenci Bolognetti, Dipartimento di Scienze Biochimiche "A. Rossi Fanelli" and Istituto di Biologia e Patologia Molecolari del CNR, Sapienza Università di Roma, 00185 Rome, Italy.
International Journal of Molecular Sciences
|December 23, 2022
Summary
Src Homology 2 (SH2) domains are crucial for cell signaling via phosphotyrosine binding. Understanding their stability and binding is key to developing new therapeutics for SH2-related diseases.
Area of Science:
- Molecular Biology
- Biochemistry
- Structural Biology
Background:
- Src Homology 2 (SH2) domains mediate critical protein-protein interactions (PPIs) by recognizing phosphorylated tyrosine residues.
- Phosphotyrosine modification is a key regulator of eukaryotic cellular pathways, highlighting the fundamental role of SH2 domains in cell signaling.
- Dysregulation of SH2 domain-mediated PPIs is implicated in various human pathologies.
Purpose of the Study:
- To review current knowledge on the structural, folding stability, and binding properties of SH2 domains.
- To elucidate the roles of SH2 domains in molecular pathways and pathogenesis.
- To explore strategies for modulating or inhibiting SH2 domain binding for therapeutic purposes.
Main Methods:
- Literature review of structural, biophysical, and biochemical studies on SH2 domains.
- Analysis of SH2 domain involvement in cellular signaling and disease mechanisms.
- Examination of diverse approaches for targeting SH2 domain interactions.
Main Results:
- SH2 domains are well-characterized PPI modules essential for signal transduction.
- Their structural and binding properties are intrinsically linked to their function in physiological and pathological processes.
- Various strategies exist to modulate SH2 domain binding, indicating therapeutic potential.
Conclusions:
- Pharmacological targeting of SH2 domains presents a strategic avenue for novel therapeutic development.
- A comprehensive understanding of SH2 domain thermodynamic stability and binding determinants is crucial for preventing dysregulated interactions and improving therapeutic efficacy.
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