Sonata19
Zn2+-dependent competition between CD4 and CD8α coreceprtor for Lck tyrosine kinase
Project number: 2023/51/D/NZ1/01979
PI: dr Anna Kocyła
Zinc as a Molecular Bridge in Immune Signaling
Cellular signaling relies heavily on precise protein interactions, which are essential for immune system function. While many of these interactions occur through direct contact, some require a molecular facilitator. Metal ions—especially zinc (Zn²⁺)—play a critical role in this context.
Zinc possesses a unique ability to bind to specific amino acid residues, acting as a dynamic stabilizer that can hold protein complexes together and release them when needed. This project investigates the molecular basis of the first known Zn²⁺-dependent protein heterodimer: the interaction between CD4/CD8 coreceptors and the tyrosine kinase Lck.
CD4 and CD8 use Zn²⁺ to anchor Lck near the T cell receptor (TCR), enabling the initiation of immune signaling. Although both coreceptors perform similar functions in Lck recruitment, they differ significantly in their amino acid sequences and define two distinct T cell populations. CD4⁺ T cells (helper cells) activate other immune cells, while CD8⁺ T cells (cytotoxic cells) directly eliminate infected targets.
Exploring Zinc-Dependent Complexes in T Cell Differentiation
CD4⁺ and CD8⁺ T cells originate from common CD4⁺CD8⁺ precursors, with Lck playing a crucial role in their developmental commitment. Since Zn²⁺ is essential for the formation of CD4/CD8-Lck complexes, this project aims to answer several key questions:
- What is the optimal Zn²⁺ concentration for stabilizing CD4-Lck and CD8-Lck interactions?
- Which amino acid residues enhance or weaken the formation of these complexes?
- How do variations in CD4/CD8-Lck complexes influence immune signaling and cell fate decisions?
To address these questions, the project integrates multiple research strategies:
- Biophysical characterization using model membranes that mimic cellular conditions.
- Yeast-based screening to identify CD4/CD8-Lck variants with different Zn²⁺ affinities.
- Cellular assays to evaluate the signaling behavior of these complexes in model cell lines.
These investigations aim to deepen our understanding of zinc-mediated immune signalling and may inform future therapeutic approaches for immune-related disorders.
