What is integrin extension?2017-12-26T15:38:24+00:00

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 pinfo family=”Integrin”]integrin[/pinfo] 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.

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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]