Limits...
Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

Chen W, Lou J, Hsin J, Schulten K, Harvey SC, Zhu C - PLoS Comput. Biol. (2011)

Bottom Line: By comparison, a fully-extended conformation was stable.A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation.These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

View Article: PubMed Central - PubMed

Affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

Show MeSH
System equilibration.A. Schematic of an extracellular portion of integrin αVβ3 showing the various domains of the αV (cyan) and β3 (pink) subunits. B. Structure of U1 in a water box used for equilibration with the integrin subunits shown in the same color scheme as in panel A. Yellow sticks represent sugars attached on the protein. Red spheres represent divalent metal ions bound to the protein. Blue dots represent water molecules. The same color codes and representations are used in all figures and videos. C. Cα RMSDs of the four simulated structures during equilibration. D. Buried SASAs between the headpiece and tailpiece of U1 during equilibration.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC3040657&req=5

pcbi-1001086-g001: System equilibration.A. Schematic of an extracellular portion of integrin αVβ3 showing the various domains of the αV (cyan) and β3 (pink) subunits. B. Structure of U1 in a water box used for equilibration with the integrin subunits shown in the same color scheme as in panel A. Yellow sticks represent sugars attached on the protein. Red spheres represent divalent metal ions bound to the protein. Blue dots represent water molecules. The same color codes and representations are used in all figures and videos. C. Cα RMSDs of the four simulated structures during equilibration. D. Buried SASAs between the headpiece and tailpiece of U1 during equilibration.

Mentions: Integrins are αβ heterodimeric transmembrane receptors for cell-cell and cell-extracellular matrix adhesions [1]. The overall shape of an integrin ectodomain is that of a large head supported by two long legs [2], [3]. The head of αA (or αI) domain-lacking integrins, including the integrin αVβ3 studied here, consists of the β-propeller domain of the α subunit and the βA (or βI) domain of the β subunit (Fig. 1A). The two legs contain the thigh domain and the calf-1 and -2 domains of the α subunit and the hybrid, plexin-semaphorin-integrin (PSI), epidermal growth factor (EGF) 1–4 domains and the β tail domain (βTD) of the β subunit.


Molecular dynamics simulations of forced unbending of integrin α(v)β₃.

Chen W, Lou J, Hsin J, Schulten K, Harvey SC, Zhu C - PLoS Comput. Biol. (2011)

System equilibration.A. Schematic of an extracellular portion of integrin αVβ3 showing the various domains of the αV (cyan) and β3 (pink) subunits. B. Structure of U1 in a water box used for equilibration with the integrin subunits shown in the same color scheme as in panel A. Yellow sticks represent sugars attached on the protein. Red spheres represent divalent metal ions bound to the protein. Blue dots represent water molecules. The same color codes and representations are used in all figures and videos. C. Cα RMSDs of the four simulated structures during equilibration. D. Buried SASAs between the headpiece and tailpiece of U1 during equilibration.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3040657&req=5

pcbi-1001086-g001: System equilibration.A. Schematic of an extracellular portion of integrin αVβ3 showing the various domains of the αV (cyan) and β3 (pink) subunits. B. Structure of U1 in a water box used for equilibration with the integrin subunits shown in the same color scheme as in panel A. Yellow sticks represent sugars attached on the protein. Red spheres represent divalent metal ions bound to the protein. Blue dots represent water molecules. The same color codes and representations are used in all figures and videos. C. Cα RMSDs of the four simulated structures during equilibration. D. Buried SASAs between the headpiece and tailpiece of U1 during equilibration.
Mentions: Integrins are αβ heterodimeric transmembrane receptors for cell-cell and cell-extracellular matrix adhesions [1]. The overall shape of an integrin ectodomain is that of a large head supported by two long legs [2], [3]. The head of αA (or αI) domain-lacking integrins, including the integrin αVβ3 studied here, consists of the β-propeller domain of the α subunit and the βA (or βI) domain of the β subunit (Fig. 1A). The two legs contain the thigh domain and the calf-1 and -2 domains of the α subunit and the hybrid, plexin-semaphorin-integrin (PSI), epidermal growth factor (EGF) 1–4 domains and the β tail domain (βTD) of the β subunit.

Bottom Line: By comparison, a fully-extended conformation was stable.A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation.These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

View Article: PubMed Central - PubMed

Affiliation: Woodruff School of Mechanical Engineering, Georgia Institute of Technology, Atlanta, Georgia, United States of America.

ABSTRACT
Integrins may undergo large conformational changes during activation, but the dynamic processes and pathways remain poorly understood. We used molecular dynamics to simulate forced unbending of a complete integrin α(v)β₃ ectodomain in both unliganded and liganded forms. Pulling the head of the integrin readily induced changes in the integrin from a bent to an extended conformation. Pulling at a cyclic RGD ligand bound to the integrin head also extended the integrin, suggesting that force can activate integrins. Interactions at the interfaces between the hybrid and β tail domains and between the hybrid and epidermal growth factor 4 domains formed the major energy barrier along the unbending pathway, which could be overcome spontaneously in ~1 µs to yield a partially-extended conformation that tended to rebend. By comparison, a fully-extended conformation was stable. A newly-formed coordination between the α(v) Asp457 and the α-genu metal ion might contribute to the stability of the fully-extended conformation. These results reveal the dynamic processes and pathways of integrin conformational changes with atomic details and provide new insights into the structural mechanisms of integrin activation.

Show MeSH