Integrin αIIbβ3 Inside-out Activation
Year: 2012
Type: article
Abstract: Integrins are a family of heterodimeric adhesion receptors that transmit signals bi-directionally across the plasma membranes. The transmembrane domain (TM) of integrin plays a critical role in mediating transition of the receptor from the default inactive to the active state on the cell surfaces. In this study, we successfully applied the substituted cysteine scanning accessibility method to determine the intracellular border of the integrin α IIb β 3 TM in the inactive and active states in living cells. We examined the aqueous accessibility of 75 substituted cysteines comprising the C terminus of both α IIb and β 3 TMs, the intracellular membrane-proximal regions, and the whole cytoplasmic tails, to the labeling of a membrane-permeable, cysteine-specific chemical biotin maleimide (BM). The active state of integrin α IIb β 3 heterodimer was generated by co-expression of activating partners with the cysteine-substituted constructs. Our data revealed that, in the inactive state, the intracellular lipid/aqueous border of α IIb TM was at Lys 994 and β 3 TM was at Phe 727 respectively; in the active state, the border of α IIb TM shifted to Pro 998 , whereas the border of β 3 TM remained unchanged, suggesting that complex conformational changes occurred in the TMs upon α IIb β 3 inside-out activation. On the basis of the results, we propose a new inside-out activation mechanism for integrin α IIb β 3 and by inference, all of the integrins in their native cellular environment. Background: The transmembrane domain of integrins plays a critical role in mediating receptor inside-out activation. Results: Inside-out activation triggers the repartitioning of the intracellular border of α IIb but not the β 3 transmembrane domain into the lipid bilayer in living cells. Conclusion: Complex conformational changes occur in the transmembrane domain upon integrin α IIb β 3 inside-out activation. Significance: Our findings represent a new mechanism for integrin inside-out activation.
Source: Journal of Biological Chemistry
Institution: University of California, Los Angeles
Language: English
Subfield: Immunology and Allergy
Field: Medicine
Domain: Health Sciences
Open Access status: hybrid
Estimated APC paid: $3,430
OpenAlex ID: W2098067260