Differences in α-β transmembrane domain interactions among integrins enable diverging integrin signaling

Integrins are transmembrane adhesion molecules composed of alpha and beta subunits. In humans, 24 integrins are expressed in a tissue-specific manner. Each integrin plays a specific role within a tissue type to control cell adhesion. We previously found that the degree of transmembrane domain (TMD) interaction between the integrin alpha IIb and beta 3 subunits is reversely correlated with the affinity of integrin alpha IIb beta 3 to its ligand. Here, we examined the TMD interactions of various integrins, including alpha 4 beta 1, alpha L beta 2, alpha 5 beta 1, alpha V beta 1, alpha IIb beta 3, and alpha V beta 3. Our findings revealed that the degree of the TMD interactions in integrins alpha 4 beta 1 and alpha L beta 2 expressed in immune cells was low and in integrins alpha IIb beta 3 and alpha V beta 3 expressed in platelets was high, while integrins alpha 5 beta 1 and alpha V beta 1 that are expressed in most adherent cells displayed intermediate TMD interactions. We identified sequence variation within the N-terminal TMD region as a factor responsible for the observed differential degree of TMD interaction among integrins. When the N-terminal interaction that was missing in integrin alpha 5 beta 1 was restored with mutagenesis, the increase in TMD interaction inhibited the outside-in but not inside-out signaling of integrin alpha 5 beta 1 and also accelerated the speed of cell migration. We suggest, therefore, that the degree of TMD interaction is designed to accommodate the specific, desired function of each integrin. (C) 2013 Elsevier Inc. All rights reserved.