Binding of a Soluble meso-Tetraarylporphyrin to Human Galectin-7 Induces Oligomerization and Modulates Its Pro-Apoptotic Activity

Abstract

The selective targeting of protein–protein interactions remains a significant determinant for the proper modulation and regulation of cell apoptosis. Prototypic galectins such as human galectin-7 (GAL-7) are characterized by their ability to form homodimers that control the molecular fate of a cell by mediating subtle yet critical glycan-dependent interactions between pro- and anti-apoptotic molecular partners. Altering the structural architecture of GAL-7 can therefore result in resistance to apoptosis in various human cancer cells, further illustrating its importance in cell survival. In this study, we used a combination of biophysical and cellular assays to illustrate that binding of a water-soluble meso-tetraarylporphyrin molecule to GAL-7 induces protein oligomerization and modulation of GAL-7-induced apoptosis in human Jurkat T cells. Our results suggest that the integrity of the GAL-7 homodimer architecture is essential for its molecular function, in addition to providing an interesting porphyrin binding modulator for controlling apoptosis in mammalian cells.

Perturbing dimer interactions and allosteric communication modulates the immunosuppressive activity of human galectin-7

“…Galectins are known to induce apoptosis of human T cells by binding to their glycosylated receptors, thereby modulating cell fate in diseases such as cancer ( 42 ). For a number of years, our group has extensively used GAL-7 as a relevant model for studying Jurkat T cell induced apoptosis, providing additional information on molecular and cellular mechanisms governing GAL-7 function in the cell ( 11 , 14 , 34 , 43 ). Despite several studies detailing the existence of a homodimeric structure in GAL-7, few reports have thus far interrogated the importance of maintaining the integrity and stability of this dimer for preservation of function.…”

“…This functional modulation further demonstrates the relevance of this protein–protein interaction as an efficient interface for future rational drug discovery programs targeting GAL-7. Indeed, many structurally homologous galectins are involved in mediating subtle yet critical glycan-dependent and -independent interactions between pro- and antiapoptotic molecular partners in the cell ( 15 , 33 , 43 ). As a result of their highly homologous GBS interactions, the specific targeting of selected galectin members remains one of the most promising avenues for future disease treatments.…”

Towards a Better Understanding of the Relationships between Galectin-7, p53 and MMP-9 during Cancer Progression

“…Given the multiple roles of galectins in controlling the tumor microenvironment, it is reasonable to hypothesize that the production and release of galectin-7 by cancer cells is one of multiple mechanisms used by GOF mutants of p53 to facilitate a protumorigenic microenvironment [40]. Such a role for galectin-7 in the tumor microenvironment would include its ability to induce local immunosuppression, as we know now that galectin-7, like many galectins, induces apoptosis in activated immune cells [37,41,42]. This role would also include the regulation of the expression of protumorigenic genes in cancer cells.…”

Functions and Inhibition of Galectin-7, an Emerging Target in Cellular Pathophysiology

“…A reduction in the ability of the protein to induce apoptosis of Jurkat T cells was observed [ 119 ]. More recently it was demonstrated that meso -tetrakis( p -sulfonatophenyl)porphyrin 27 (TpSPPH 2 , Figure 9 ) significantly reduced the level of (galectin-7-induced) apoptosis of human Jurkat T cells [ 120 ].…”

“…Docking simulations on galectin-7 showed that the TpSPPH 2 moiety preferentially binds to three main subsites at the dimer interface. [ 120 ].…”