Description
Understanding protein structure is essential for elucidating disease mechanisms such as cancer, Alzheimer's disease, and type II diabetes. Among these proteins, the tumor suppressor p53 is particularly critical: its inactivation or mutation occurs in approximately 50% of human cancers. Functioning as a tetramer, p53 regulates DNA repair, cell-cycle arrest, and apoptosis—processes that maintain genomic stability and prevent uncontrolled proliferation. However, upon mutation, p53 can misfold and aggregate, forming amyloid-like structures that may cause loss-of-function or gain-of-toxic-function phenotypes. Despite over 30 years of research, the mechanisms of p53 aggregation and the organization of secondary structures within aggregates remain unclear, largely due to the lack of label-free techniques capable of probing these structural features in real time.
To advance therapeutics and fundamental understanding, the nonlinear optical tools coherent and incoherent Second Harmonic Generation (SHG) were employed to probe the structural properties of p53 aggregates. Coherent and incoherent SHG generate signals exclusively from non-centrosymmetric media, making them sensitive to the ordered β-sheet structures within p53 aggregates. This inherent selectivity arises from photon scattering by anisotropic molecular assemblies, enabling direct, label-free readout of structural order without external perturbation. Therefore, while coherent SHG provides macroscopic information on the assembly of protein aggregates, incoherent SHG offers complementary insights into individual protein aggregate, revealing the heterogeneity within the population.
We will present coherent SHG measurements that quantify the extent of β-sheet aggregation in elongated fibrils (exhibiting higher anisotropy), alongside incoherent SHG signatures that allow us to detect signals from tangled oligomers (characterized by low anisotropy). We will show how these combined measurements enable a dynamic, label-free, and structurally sensitive study of p53 aggregates. These observational techniques have the potential to improve understanding of the relationship between p53 conformation, molecular interactions, and biological function.
| I am the presenting author | Yes |
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