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A MD Simulation Prediction for Regulation of N-Terminal Modification on Binding of CD47 to CD172a in a
Yang Zhao1, Liping Fang1, Pei Guo1
1Institute of Biomechanics, School of Biology and Biological Engineering, South China University of Technology, Guangzhou 510006, China.
Abstract:
Cancer cells can evade immune surveillance through binding of its transmembrane receptor CD47 to CD172a on myeloid cells. CD47 is recognized as a promising immune checkpoint for cancer immunotherapy inhibiting macrophage phagocytosis. N-terminal post-translated modification (PTM) via glutaminyl cyclase is a landmark event in CD47 function maturation, but the molecular mechanism underlying the mechano-chemical regulation of the modification on CD47/CD172a remains unclear. Here, we performed so-called "ramp-clamp" steered molecular dynamics (SMD) simulations, and found that the N-terminal PTM enhanced interaction of CD172a with CD47 by inducing a dynamics-driven contraction of the binding pocket of the bound CD172a, an additional constraint on CYS15 on CD47 significantly improved the tensile strength of the complex with or without PTM, and a catch bond phenomenon would occur in complex dissociation under tensile force of 25 pN in a PTM-independent manner too. The residues GLN52 and SER66 on CD172a reinforced the H-bonding with their partners on CD47 in responding to PTM, while ARG69 on CD172 with its partner on CD47 might be crucial in the structural stability of the complex. This work might serve as molecular basis for the PTM-induced function improvement of CD47, should be helpful for deeply understanding CD47-relevant immune response and cancer development, and provides a novel insight in developing of new strategies of immunotherapy targeting this molecule interaction.
Insights
Cancer cells evade immune surveillance via CD47 binding to CD172a. N-terminal post-translated modification (PTM) enhances this interaction, offering potential for novel cancer immunotherapies targeting CD47.
Area of Science:
- Immunology
- Molecular Biology
- Computational Biophysics
Background:
- Cancer cells utilize CD47-CD172a interactions to evade immune surveillance, inhibiting macrophage phagocytosis.
- CD47 is a key target for cancer immunotherapy, with N-terminal post-translated modification (PTM) being crucial for its function.
Purpose of the Study:
- To elucidate the molecular mechanism of mechano-chemical regulation of CD47/CD172a interaction following N-terminal PTM.
- To understand how PTM influences the binding dynamics and tensile strength of the CD47-CD172a complex.
Main Methods:
- Steered molecular dynamics (SMD) simulations, including ramp-clamp simulations, were employed.
- Analysis focused on binding pocket dynamics, tensile strength, and key residue interactions.
Main Results:
- N-terminal PTM enhances CD47-CD172a interaction by contracting the CD172a binding pocket.
- A catch bond phenomenon was observed during complex dissociation, independent of PTM.
- Specific residues (GLN52, SER66, ARG69) on CD172a play critical roles in PTM response and complex stability.
Conclusions:
- PTM of CD47 enhances its interaction with CD172a through dynamic structural changes.
- This study provides a molecular basis for PTM-induced CD47 function enhancement.
- Findings offer insights for developing new cancer immunotherapy strategies targeting the CD47-CD172a axis.
