Mechanosignaling

What is integrin extension?

Integrin extension

Upon alteration in the transmembrane and their proximal domains, the bent headpiece extends in less than 1 second [1] with intermediate affinity for ligands. Two models- “switchblade” and “deadbolt”- have been proposed for the mechanism of transmission of signals from across the plasma membrane leading to extension (reviewed in [2][3]).

According to the former model, leg separation causes a jackknife-like extension of the knee that releases the hybrid domain from the constraint of the bent form [4][5]. The latter model postulates that the activated integrin remains in a bent state (even with bound ligand) until the interaction between the headpiece and the β-stalk is disrupted by piston-like movement of TM domains and sliding of the extracellular stalks [6].

Subsequent opening of the βA/hybrid domain hinge happens by spontaneous swing out of the hybrid domain and thus the integrin dimer becomes competent for ligand binding [7]. In immunologically relevant integrins, serine phosphorylation of integrin α subunit has also been shown as a critical criterion for αI conformation changes for ligand binding [8][9].

Tension generated by the interplay of cytoskeletal forces and ECM stiffness has been shown to be sufficient for mechanical activation of integrins to aid cell motility [10]. Nevertheless, they are believed to constantly switch between ligand bound active and unbound inactive states, thus conferring the focal adhesions with distinct dynamics so as to endure rapid changes in force [11]. Also, bent integrins that move along the cell membrane may collide with other membrane proteins and this could result in structural changes [12]. However, further structural studies in physiologically relevant conditions are required to substantially establish this theory.

References

1. Shimaoka M, Takagi J, and Springer TA. Conformational regulation of integrin structure and function. Annu Rev Biophys Biomol Struct 2001; 31:485-516. [PMID: 11988479]
2. Luo B, Carman CV, and Springer TA. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 2007; 25:619-47. [PMID: 17201681]
3. Arnaout MA, Mahalingam B, and Xiong J. Integrin structure, allostery, and bidirectional signaling. Annu. Rev. Cell Dev. Biol. 2005; 21:381-410. [PMID: 16212500]
4. Takagi J, Petre BM, Walz T, and Springer TA. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 2002; 110(5):599-11. [PMID: 12230977]
5. Lefort CT, Hyun Y, Schultz JB, Law F, Waugh RE, Knauf PA, and Kim M. Outside-in signal transmission by conformational changes in integrin Mac-1. J. Immunol. 2009; 183(10):6460-8. [PMID: 19864611]
6. Adair BD, Xiong J, Maddock C, Goodman SL, Arnaout MA, and Yeager M. Three-dimensional EM structure of the ectodomain of integrin {alpha}V{beta}3 in a complex with fibronectin. J. Cell Biol. 2005; 168(7):1109-18. [PMID: 15795319]
7. Puklin-Faucher E, Gao M, Schulten K, and Vogel V. How the headpiece hinge angle is opened: New insights into the dynamics of integrin activation. J. Cell Biol. 2006; 175(2):349-60. [PMID: 17060501]
8. Fagerholm SC, Hilden TJ, Nurmi SM, and Gahmberg CG. Specific integrin alpha and beta chain phosphorylations regulate LFA-1 activation through affinity-dependent and -independent mechanisms. J. Cell Biol. 2005; 171(4):705-15. [PMID: 16301335]
9. Fagerholm SC, Varis M, Stefanidakis M, Hilden TJ, and Gahmberg CG. alpha-Chain phosphorylation of the human leukocyte CD11b/CD18 (Mac-1) integrin is pivotal for integrin activation to bind ICAMs and leukocyte extravasation. Blood 2006; 108(10):3379-86. [PMID: 16857989]
10. Friedland JC, Lee MH, and Boettiger D. Mechanically activated integrin switch controls alpha5beta1 function. Science 2009; 323(5914):642-4. [PMID: 19179533]
11. Ivaska J. Unanchoring integrins in focal adhesions. Nat. Cell Biol. 2012; 14(10):981-3. [PMID: 23033047]
12. Zhu J, Luo B, Xiao T, Zhang C, Nishida N, and Springer TA. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell 2008; 32(6):849-61. [PMID: 19111664]