Parsing digital or analog TCR performance through piconewton forces

Akitsu, Aoi; Kobayashi, Eiji; Feng, Yinnian; Stephens, Hannah M.; Brazin, Kristine N.; Masi, Daniel J.; Kirkpatrick, Evan H.; Mallis, Robert J.; Duke-Cohan, Jonathan S.; Booker, Matthew A.; Cinella, Vincenzo; Feng, William W.; Holliday, Elizabeth L.; Lee, Jonathan J.; Zienkiewicz, Katarzyna J.; Tolstorukov, Michael Y.; Hwang, Wonmuk; Lang, Matthew J.; Reinherz, Ellis L.

doi:10.1126/sciadv.ado4313

Sci. Adv.

2024

DOI: 10.1126/sciadv.ado4313

|View full text |Cite

Parsing digital or analog TCR performance through piconewton forces

Aoi Akitsu,

Eiji Kobayashi,

Yinnian Feng

et al.

Abstract: αβ T cell receptors (TCRs) principally recognize aberrant peptides bound to major histocompatibility complex molecules (pMHCs) on unhealthy cells, amplifying specificity and sensitivity through physical load placed on the TCR-pMHC bond during immunosurveillance. To understand this mechanobiology, TCRs stimulated by abundantly and sparsely arrayed epitopes (NP 366–374 /D b and PA 224–233 /D b , respectively) followin… Show more

Help me understand this report

Search citation statements

Order By: Relevance

Paper Sections

Select...

Citation Types

Supporting

Mentioning

Contrasting

Year Published

2024

Publication Types

Select...

Preprint3

Relationship

Self Cite0

Independent3

Authors

Journals

Cited by 3 publications

References 69 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Chang-Gonzalez,

Akitsu,

Mallis

et al. 2024

Preprint

View full text Add to dashboard Cite

Increasing evidence suggests that mechanical load on the αβ T cell receptor (TCR) is crucial for recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination. To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ~15-pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC during the simulation. These results suggest that the dynamic allostery common to the TCRαβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and potentially nuanced biological outcomes.

show abstract

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Chang-Gonzalez,

Akitsu,

Mallis

et al. 2024

Preprint

View full text Add to dashboard Cite

show abstract

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Chang-Gonzalez,

Akitsu,

Mallis

et al. 2024

Preprint

View full text Add to dashboard Cite

Increasing evidence suggests that mechanical load on the αβ T cell receptor (TCR) is crucial for recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination. To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15-pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC during the simulation. These results suggest that the dynamic allostery common to the TCR αβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and potentially nuanced biological outcomes.

show abstract

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Chang-Gonzalez,

Akitsu,

Mallis

et al. 2024

Preprint

View full text Add to dashboard Cite

Increasing evidence suggests that mechanical load on the αβ T cell receptor (TCR) is crucial for recognizing the antigenic peptide-loaded major histocompatibility complex (pMHC) molecule. Our recent all-atom molecular dynamics (MD) simulations revealed that the inter-domain motion of the TCR is responsible for the load-induced catch bond behavior of the TCR-pMHC complex and peptide discrimination. To further examine the generality of the mechanism, we perform all-atom MD simulations of the B7 TCR under different conditions for comparison with our previous simulations of the A6 TCR. The two TCRs recognize the same pMHC and have similar interfaces with pMHC in crystal structures. We find that the B7 TCR-pMHC interface stabilizes under ∼15-pN load using a conserved dynamic allostery mechanism that involves the asymmetric motion of the TCR chassis. However, despite forming comparable contacts with pMHC as A6 in the crystal structure, B7 has fewer high-occupancy contacts with pMHC during the simulation. These results suggest that the dynamic allostery common to the TCR αβ chassis can amplify slight differences in interfacial contacts into distinctive mechanical responses and potentially nuanced biological outcomes.

show abstract

scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.

Contact Info

customersupport@researchsolutions.com

10624 S. Eastern Ave., Ste. A-614

Henderson, NV 89052, USA

This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.

Blog Terms and Conditions API Terms Privacy Policy Contact Cookie Preferences Do Not Sell or Share My Personal Information

Made with 💙 for researchers

Part of the Research Solutions Family.

Parsing digital or analog TCR performance through piconewton forces

Cited by 3 publications

References 69 publications

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Load-based divergence in the dynamic allostery of two TCRs recognizing the same pMHC

Contact Info

Product

Resources

About