- 作者: Halina Z Malina
- 作者服務機構: MalinaLab-Axanton, Tiefenaustr.110, CH-3004 Bern, Switzerland
- 中文摘要: --
- 英文摘要:
Background: The physiological processes in the cell are regulated by reversible, electrostatic
protein-protein interactions. Apoptosis is such a regulated process, which is critically
important in tissue homeostasis and development and leads to complete disintegration of the
cell. Pathological apoptosis, a process similar to apoptosis, is associated with aging and
infection. The current study shows that pathological apoptosis is a process caused by the
covalent interactions between the signaling proteins, and a characteristic of this pathological
network is the covalent binding of calmodulin to regulatory sequences.
Results: Small molecules able to bind covalently to the amino group of lysine, histidine,
arginine, or glutamine modify the regulatory sequences of the proteins. The present study
analyzed the interaction of calmodulin with the BH3 sequence of Bax, and the calmodulinbinding
sequence of myristoylated alanine-rich C-kinase substrate in the presence of
xanthurenic acid in primary retinal epithelium cell cultures and murine epithelial fibroblast
cell lines transformed with SV40 (wild type [WT], Bid knockout [Bid-/-], and Bax-/-/Bak-/-
double knockout [DKO]). Cell death was observed to be associated with the covalent binding
of calmodulin, in parallel, to the regulatory sequences of proteins. Xanthurenic acid is known
to activate caspase-3 in primary cell cultures, and the results showed that this activation is
also observed in WT and Bid-/- cells, but not in DKO cells. However, DKO cells were not
protected against death, but high rates of cell death occurred by detachment.
Conclusions: The results showed that small molecules modify the basic amino acids in the
regulatory sequences of proteins leading to covalent interactions between the modified
sequences (e.g., calmodulin to calmodulin-binding sites). The formation of these polymers
(aggregates) leads to an unregulated and, consequently, pathological protein network. The results suggest a mechanism for the involvement of small molecules in disease development.
In the knockout cells, incorrect interactions between proteins were observed without the
protein modification by small molecules, indicating the abnormality of the protein network in
the transgenic system. The irreversible protein-protein interactions lead to protein aggregation
and cell degeneration, which are observed in all aging-associated diseases. - 中文關鍵字: --
- 英文關鍵字: --