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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.

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Changes in hinge angles at the α/β knees during unbending.A & B. Time courses of thigh/calf-1 (red), EGF1/EGF2 (blue), and EGF2/EGF3 (pink) hinge angles in the U1 SMD 1 (A) and U2 SMD (B). C & D. The EGF1/EGF2 (red squares) and EGF2/EGF3 (blue circles) hinge angles are plotted against the thigh/calf-1 hinge angle for the U1 SMD 1 (C) and U2 SMD (D). Solid lines are fits to the linear regions.
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pcbi-1001086-g005: Changes in hinge angles at the α/β knees during unbending.A & B. Time courses of thigh/calf-1 (red), EGF1/EGF2 (blue), and EGF2/EGF3 (pink) hinge angles in the U1 SMD 1 (A) and U2 SMD (B). C & D. The EGF1/EGF2 (red squares) and EGF2/EGF3 (blue circles) hinge angles are plotted against the thigh/calf-1 hinge angle for the U1 SMD 1 (C) and U2 SMD (D). Solid lines are fits to the linear regions.

Mentions: To examine whether the forced extension of the two knees occurred cooperatively, we analyzed three hinge angles: the thigh/calf-1 hinge angle for the α-knee and the EGF1/EGF2 and EGF2/EGF3 hinge angles for the β-knee (Figs. 5 and S3). Both the EGF1/EGF2 and EGF2/EGF3 hinges are bent in the starting structure of U1 (where the EGF1 and EGF2 domains were modeled) (Fig. S4); hence, these hinge angles opened significantly during integrin extension. In the starting structure of U2, by comparison, the β-knee is mainly bent at the EGF1/EGF2 hinge and hence this was where the major angle changes occurred. The hinge angles for the α- and β-knees increased with increasing head-tail extension concurrently (Figs. 5 and S3 A & B). To examine their cooperation, different hinge angles were plotted against each other, which reveal linear relationships until the integrin was over-stretched beyond the point where the integrin was fully straightened and the flexible EGF domains began to rotate about different hinges (Figs. 5 and S3 C & D). These results indicate that the interactions that hold the α/β knees in the bent conformation are cooperative.


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)

Changes in hinge angles at the α/β knees during unbending.A & B. Time courses of thigh/calf-1 (red), EGF1/EGF2 (blue), and EGF2/EGF3 (pink) hinge angles in the U1 SMD 1 (A) and U2 SMD (B). C & D. The EGF1/EGF2 (red squares) and EGF2/EGF3 (blue circles) hinge angles are plotted against the thigh/calf-1 hinge angle for the U1 SMD 1 (C) and U2 SMD (D). Solid lines are fits to the linear regions.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1001086-g005: Changes in hinge angles at the α/β knees during unbending.A & B. Time courses of thigh/calf-1 (red), EGF1/EGF2 (blue), and EGF2/EGF3 (pink) hinge angles in the U1 SMD 1 (A) and U2 SMD (B). C & D. The EGF1/EGF2 (red squares) and EGF2/EGF3 (blue circles) hinge angles are plotted against the thigh/calf-1 hinge angle for the U1 SMD 1 (C) and U2 SMD (D). Solid lines are fits to the linear regions.
Mentions: To examine whether the forced extension of the two knees occurred cooperatively, we analyzed three hinge angles: the thigh/calf-1 hinge angle for the α-knee and the EGF1/EGF2 and EGF2/EGF3 hinge angles for the β-knee (Figs. 5 and S3). Both the EGF1/EGF2 and EGF2/EGF3 hinges are bent in the starting structure of U1 (where the EGF1 and EGF2 domains were modeled) (Fig. S4); hence, these hinge angles opened significantly during integrin extension. In the starting structure of U2, by comparison, the β-knee is mainly bent at the EGF1/EGF2 hinge and hence this was where the major angle changes occurred. The hinge angles for the α- and β-knees increased with increasing head-tail extension concurrently (Figs. 5 and S3 A & B). To examine their cooperation, different hinge angles were plotted against each other, which reveal linear relationships until the integrin was over-stretched beyond the point where the integrin was fully straightened and the flexible EGF domains began to rotate about different hinges (Figs. 5 and S3 C & D). These results indicate that the interactions that hold the α/β knees in the bent conformation are cooperative.

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