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Updated: May 22, 2025
Spatiotemporal Control of Protein Activity through Optogenetic Allosteric Regulation
Published on: October 4, 2024
Lipid-driven Src self-association modulates its transformation capacity
Irrem-Laareb Mohammad1, Marina I Giannotti2,3,4, Elise Fourgous5,6
1https://ror.org/021018s57 Biomolecular NMR Laboratory, Department of Inorganic and Organic Chemistry, Universitat de Barcelona (UB), Barcelona, Spain.
Abstract:
Src tyrosine kinase regulates cell growth and adhesion through membrane signaling, and its deregulation is associated with cancer. Although active Src is anchored to the plasma membrane, the role of membrane lipids in its regulation remains unclear. Here, we report that Src self-associates via a lysine cluster in its SH4 region, a process mediated by lipids in human cells and in vitro. Mutation of the lysine cluster to arginine alters Src self-association and modulates its transforming function in human cells. Lipid-anchored micron-sized condensates of full-length Src form in supported homogeneous lipid bilayers (i.e., independently of lipid phase separation). Condensates also arise from the purified Src N-terminal regulatory element, which includes the myristoylated SH4 domain, the intrinsically disordered Unique domain, and the globular SH3 domain. However, the isolated SH4 domain alone forms small protein-lipid clusters rather than micron-sized condensates. Our findings reveal lipid-mediated kinase self-association as an additional regulatory mechanism for Src. This mechanism may also apply to other membrane-associated signaling proteins containing similar lysine clusters in their unstructured regions.
Insights
Membrane lipids regulate Src tyrosine kinase self-association through a lysine cluster in its SH4 region, impacting cell growth and cancer. This lipid-mediated mechanism may extend to other signaling proteins.
Area of Science:
- Biochemistry
- Cell Biology
- Molecular Oncology
Background:
- Src tyrosine kinase is crucial for cell growth and adhesion, with deregulation linked to cancer.
- While Src associates with the plasma membrane, the influence of membrane lipids on its regulation is not well understood.
Purpose of the Study:
- To investigate the role of membrane lipids in regulating Src tyrosine kinase activity and self-association.
- To elucidate the structural basis and functional consequences of lipid-mediated Src self-association.
Main Methods:
- In vitro and in vivo assays using human cells to study Src self-association.
- Site-directed mutagenesis of the lysine cluster in the Src SH4 region.
- Formation of protein-lipid condensates using supported lipid bilayers and purified Src domains.
Main Results:
- Src self-associates via a lipid-mediated lysine cluster in its SH4 region.
- Mutating the lysine cluster affects Src self-association and its transforming potential in human cells.
- Full-length Src and its N-terminal regulatory element form micron-sized, lipid-anchored condensates, while the isolated SH4 domain forms smaller clusters.
Conclusions:
- Lipid-mediated kinase self-association is a novel regulatory mechanism for Src tyrosine kinase.
- This mechanism, involving lysine clusters and membrane lipids, may be relevant for other membrane-associated signaling proteins.
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