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Conformational changes in talin on binding to anionic phospholipid membranes facilitate signaling by integrin transmembrane helices.

Kalli AC, Campbell ID, Sansom MS - PLoS Comput. Biol. (2013)

Bottom Line: The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop.Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane.A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four sub-domains (F0, F1, F2 and F3) with a long cationic loop inserted in the F1 domain. Here, we model the binding and interactions of the complete talin head domain with a phospholipid bilayer, using multiscale molecular dynamics simulations. The role of the inserted F1 loop, which is missing from the crystal structure of the talin head, PDB:3IVF, is explored. The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop. Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane. Simulations of the complex of talin with the integrin α/β TM helix dimer in a membrane, show how this complex promotes a rearrangement, and eventual dissociation of, the integrin α and β transmembrane helices. A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.

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Simulation of talin in water (tal-sol-AT; see Table 1).A. Change in the angle of the F0–F1 pair relative to the F2–F3 pair from its initial position (i.e. the crystal structure) during a simulation in aqueous solution. The definition of the angle is shown in the inset. For this calculation two vectors were used: vector one was defined from the center of mass of the backbone particles of the F3 subdomain to the center of mass of the backbone particles of the F2 242–248/283–295 residue region. Similarly, vector two was defined from the center of mass of the backbone particles of the F0 subdomain to the center of mass of the backbone particles of F2 (residues 242–248/283–295). The angle displayed is the difference between the angle formed by these two vectors in the crystal structure and the angle formed by the two vectors in each snapshot of the simulation. B. Distance between the F1 loop (residue: L145) and the talin F0 domain (residue: G11) during the same simulation. The position of the loop is shown in the inset pictures at different time points.
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pcbi-1003316-g003: Simulation of talin in water (tal-sol-AT; see Table 1).A. Change in the angle of the F0–F1 pair relative to the F2–F3 pair from its initial position (i.e. the crystal structure) during a simulation in aqueous solution. The definition of the angle is shown in the inset. For this calculation two vectors were used: vector one was defined from the center of mass of the backbone particles of the F3 subdomain to the center of mass of the backbone particles of the F2 242–248/283–295 residue region. Similarly, vector two was defined from the center of mass of the backbone particles of the F0 subdomain to the center of mass of the backbone particles of F2 (residues 242–248/283–295). The angle displayed is the difference between the angle formed by these two vectors in the crystal structure and the angle formed by the two vectors in each snapshot of the simulation. B. Distance between the F1 loop (residue: L145) and the talin F0 domain (residue: G11) during the same simulation. The position of the loop is shown in the inset pictures at different time points.

Mentions: The principal simulations underlying the current study are summarized in Table 1 and in Fig. 2. The talin head domain crystal structure (PDB:3IVF [17]) lacks a long loop region in the F1 domain and therefore atomistic simulations of the talin head domain (tal-sol-AT) in solution were first used to explore potential internal flexibility between the four component sub-domains (F0–F3) along with possible conformations of the F1 domain insertion. For these simulations the insertion in the F1 domain (res: 134–172) was modeled in a random coil conformation, and was located away from the F0–F1 pair (see Fig. 3B and Fig. S1A) using Modeller 9v8 (http://salilab.org/modeller/) [43], [44]. This configuration of the loop allows exploration of all possible conformations/orientations and selection of a preferred conformation/orientation relative to the talin head domain.


Conformational changes in talin on binding to anionic phospholipid membranes facilitate signaling by integrin transmembrane helices.

Kalli AC, Campbell ID, Sansom MS - PLoS Comput. Biol. (2013)

Simulation of talin in water (tal-sol-AT; see Table 1).A. Change in the angle of the F0–F1 pair relative to the F2–F3 pair from its initial position (i.e. the crystal structure) during a simulation in aqueous solution. The definition of the angle is shown in the inset. For this calculation two vectors were used: vector one was defined from the center of mass of the backbone particles of the F3 subdomain to the center of mass of the backbone particles of the F2 242–248/283–295 residue region. Similarly, vector two was defined from the center of mass of the backbone particles of the F0 subdomain to the center of mass of the backbone particles of F2 (residues 242–248/283–295). The angle displayed is the difference between the angle formed by these two vectors in the crystal structure and the angle formed by the two vectors in each snapshot of the simulation. B. Distance between the F1 loop (residue: L145) and the talin F0 domain (residue: G11) during the same simulation. The position of the loop is shown in the inset pictures at different time points.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3814715&req=5

pcbi-1003316-g003: Simulation of talin in water (tal-sol-AT; see Table 1).A. Change in the angle of the F0–F1 pair relative to the F2–F3 pair from its initial position (i.e. the crystal structure) during a simulation in aqueous solution. The definition of the angle is shown in the inset. For this calculation two vectors were used: vector one was defined from the center of mass of the backbone particles of the F3 subdomain to the center of mass of the backbone particles of the F2 242–248/283–295 residue region. Similarly, vector two was defined from the center of mass of the backbone particles of the F0 subdomain to the center of mass of the backbone particles of F2 (residues 242–248/283–295). The angle displayed is the difference between the angle formed by these two vectors in the crystal structure and the angle formed by the two vectors in each snapshot of the simulation. B. Distance between the F1 loop (residue: L145) and the talin F0 domain (residue: G11) during the same simulation. The position of the loop is shown in the inset pictures at different time points.
Mentions: The principal simulations underlying the current study are summarized in Table 1 and in Fig. 2. The talin head domain crystal structure (PDB:3IVF [17]) lacks a long loop region in the F1 domain and therefore atomistic simulations of the talin head domain (tal-sol-AT) in solution were first used to explore potential internal flexibility between the four component sub-domains (F0–F3) along with possible conformations of the F1 domain insertion. For these simulations the insertion in the F1 domain (res: 134–172) was modeled in a random coil conformation, and was located away from the F0–F1 pair (see Fig. 3B and Fig. S1A) using Modeller 9v8 (http://salilab.org/modeller/) [43], [44]. This configuration of the loop allows exploration of all possible conformations/orientations and selection of a preferred conformation/orientation relative to the talin head domain.

Bottom Line: The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop.Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane.A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry, University of Oxford, Oxford, United Kingdom.

ABSTRACT
Integrins are heterodimeric (αβ) cell surface receptors that are activated to a high affinity state by the formation of a complex involving the α/β integrin transmembrane helix dimer, the head domain of talin (a cytoplasmic protein that links integrins to actin), and the membrane. The talin head domain contains four sub-domains (F0, F1, F2 and F3) with a long cationic loop inserted in the F1 domain. Here, we model the binding and interactions of the complete talin head domain with a phospholipid bilayer, using multiscale molecular dynamics simulations. The role of the inserted F1 loop, which is missing from the crystal structure of the talin head, PDB:3IVF, is explored. The results show that the talin head domain binds to the membrane predominantly via cationic regions on the F2 and F3 subdomains and the F1 loop. Upon binding, the intact talin head adopts a novel V-shaped conformation which optimizes its interactions with the membrane. Simulations of the complex of talin with the integrin α/β TM helix dimer in a membrane, show how this complex promotes a rearrangement, and eventual dissociation of, the integrin α and β transmembrane helices. A model for the talin-mediated integrin activation is proposed which describes how the mutual interplay of interactions between transmembrane helices, the cytoplasmic talin protein, and the lipid bilayer promotes integrin inside-out activation.

Show MeSH
Related in: MedlinePlus