All-atom simulations reveal the effect of membrane composition on the signaling of the NKG2A/CD94/HLA-E immune receptor complex

Ljubič, Martin (avtor), Perdih, Andrej (avtor), Borišek, Jure (avtor)

Understanding how membrane composition influences the dynamics and function of transmembrane proteins is crucial for the comprehensive elucidation of cellular signaling mechanisms and the development of targeted therapeutics. In this study, we employed all-atom molecular dynamics simulations to investigate the impact of different membrane compositions on the conformational dynamics of the NKG2A/CD94/HLA-E immune receptor complex, a key negative regulator of natural killer cell cytotoxic activity. Our results reveal significant variations in the behavior of the immune complex structure across five different membrane compositions, which include POPC, POPA, DPPC, and DLPC phospholipids, and a mixed POPC/cholesterol system. These variations are particularly evident in the intracellular domain of NKG2A, manifested as changes in mobility, tyrosine exposure, and interdomain communication. Additionally, we found that a large concentration of negative charge at the surface of the POPA-based membrane greatly increased the number of contacts with lipid molecules and significantly decreased the exposure of intracellular NKG2A ITIM regions to water molecules, thus likely halting the signal transduction process. Furthermore, the DPPC model with a membrane possessing a high transition temperature in a gel-like state became curved, affecting the exposure of one ITIM region. The decreased membrane thickness in the DPLC model caused a significant transmembrane domain tilt, altering the linker protrusion angle and potentially disrupting the hydrogen bonding network in the extracellular domain. Overall, our findings highlight the importance of considering membrane composition in the analysis of transmembrane protein dynamics and in the exploration of novel strategies for the external modulation of their signaling pathways.

• Jezik: Angleški jezik
• Ključne besede: cell signaling, lipids, membranes, peptides and proteins, receptors
• Vrsta gradiva: Članek v reviji
• Tipologija: 1.01 - Izvirni znanstveni članek
• Organizacija: FFA - Fakulteta za farmacijo
• Status publikacije: Objavljeno
• Različica publikacije: Objavljena publikacija
• Leto izida: 2024
• Št. strani: Str. 9374–9387
• Številčenje: Vol. 64, iss. 24
• PID: 20.500.12556/RUL-166315
• UDK: 577
• ISSN pri članku: 1549-960X
• DOI: 10.1021/acs.jcim.4c01357
• COBISS.SI-ID: 220054787
• Datum objave v RUL: 07.01.2025

Gradivo je del revije

• Naslov: Journal of chemical information and modeling
• Založnik: American Chemical Society
• ISSN: 1549-960X
• COBISS.SI-ID: 3037204

Licence

• Licenca: CC BY 4.0, Creative Commons Priznanje avtorstva 4.0 Mednarodna
• Povezava: http://creativecommons.org/licenses/by/4.0/deed.sl
• Opis: To je standardna licenca Creative Commons, ki daje uporabnikom največ možnosti za nadaljnjo uporabo dela, pri čemer morajo navesti avtorja.

Sekundarni jezik

• Jezik: Slovenski jezik
• Ključne besede: biokemija, proteini, beljakovine, membrane, molekulska dinamika