Distinct extracellular architectures shape mechanical persistence in GPVI and CLEC-2 receptor assemblies
- 1School of Mathematics and Statistics, Nantong University, Nantong, China.
- 2Laboratory of Biostatistics and Computational Medicine, Nantong University, Nantong, China.
Abstract
Glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) are platelet-activating receptors whose extracellular organization contributes to receptor association and signaling during thrombus formation, yet how alternative receptor architectures influence mechanical persistence remains unclear. We used molecular dynamics to compare a GPVI dimer based on 2GI7, a domain-swapped GPVI assembly derived from 7NMU, and a crystallographic CLEC-2 contact using the same pulling protocol and constant-force conditions. During the first 5 nm of imposed separation, reconstructed GPVI required less force and mechanical work than CLEC-2 and domain-swapped GPVI. Under constant-force loading from 400 to 600 pN, reconstructed GPVI also reached the same extension endpoint markedly earlier than the domain-swapped assembly, with passage times differing by more than an order of magnitude under several conditions. Extended pulling to approximately 10 nm produced complete loss of interreceptor heavy-atom contacts in reconstructed GPVI while local peptide and disulfide connectivity remained intact. In contrast, the domain-swapped preparation retained resistance over a larger part of the separation pathway and showed substantially greater mechanical persistence. These results show that alternative extracellular arrangements of the same receptor are not mechanically equivalent and that uncertainty in GPVI architecture can translate into large differences in force transmission and persistence under load. Such architecture-dependent persistence may influence the stability of extracellular receptor associations during thrombus formation and thereby affect the mechanical lifetime of receptor clusters under load. Author summary: Platelets form clots by recognizing molecules around them and organizing surface receptors into signaling assemblies. Two important platelet receptors, glycoprotein VI (GPVI) and CLEC-2, can experience mechanical forces as platelets interact with their surroundings during thrombus formation. GPVI has been observed in different extracellular arrangements, but it is not clear whether these structures respond differently when mechanical forces tend to pull associated receptors apart.
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BibTeX
@article{zhang2026distinct,
title = {{Distinct extracellular architectures shape mechanical persistence in GPVI and CLEC-2 receptor assemblies}},
author = {Yao Zhang and Yue Cheng and Han Ni Soe and Zhipeng Xu},
journal = {PLOS Computational Biology},
year = {2026},
month = oct,
doi = {10.1371/journal.pcbi.1014884},
url = {https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014884},
note = {CC BY},
}
RIS
TY - JOUR
TI - Distinct extracellular architectures shape mechanical persistence in GPVI and CLEC-2 receptor assemblies
AU - Yao Zhang
AU - Yue Cheng
AU - Han Ni Soe
AU - Zhipeng Xu
PY - 2026
DA - 2026/10/13
JO - PLOS Computational Biology
DO - 10.1371/journal.pcbi.1014884
UR - https://journals.plos.org/ploscompbiol/article?id=10.1371/journal.pcbi.1014884
AB - Glycoprotein VI (GPVI) and C-type lectin-like receptor 2 (CLEC-2) are platelet-activating receptors whose extracellular organization contributes to receptor association and signaling during thrombus formation, yet how alternative receptor architectures influence mechanical persistence remains unclear. We used molecular dynamics to compare a GPVI dimer based on 2GI7, a domain-swapped GPVI assembly derived from 7NMU, and a crystallographic CLEC-2 contact using the same pulling protocol and constant-force conditions. During the first 5 nm of imposed separation, reconstructed GPVI required less force and mechanical work than CLEC-2 and domain-swapped GPVI. Under constant-force loading from 400 to 600 pN, reconstructed GPVI also reached the same extension endpoint markedly earlier than the domain-swapped assembly, with passage times differing by more than an order of magnitude under several conditions. Extended pulling to approximately 10 nm produced complete loss of interreceptor heavy-atom contacts in reconstructed GPVI while local peptide and disulfide connectivity remained intact. In contrast, the domain-swapped preparation retained resistance over a larger part of the separation pathway and showed substantially greater mechanical persistence. These results show that alternative extracellular arrangements of the same receptor are not mechanically equivalent and that uncertainty in GPVI architecture can translate into large differences in force transmission and persistence under load. Such architecture-dependent persistence may influence the stability of extracellular receptor associations during thrombus formation and thereby affect the mechanical lifetime of receptor clusters under load. Author summary: Platelets form clots by recognizing molecules around them and organizing surface receptors into signaling assemblies. Two important platelet receptors, glycoprotein VI (GPVI) and CLEC-2, can experience mechanical forces as platelets interact with their surroundings during thrombus formation. GPVI has been observed in different extracellular arrangements, but it is not clear whether these structures respond differently when mechanical forces tend to pull associated receptors apart.
SN - 1553-7358
SN - 1553-734X
ER -