Researchers Reveal Novel Mechanism Underlying Integrin-mediated Lymphocyte Rolling Adhesion

The immune surveillance and host defense depend on the trafficking of lymphocytes from the blood circulation to different tissues. Lymphocytes homing to the gut is mainly mediated by a cell adhesion molecule named integrin α₄β₇. Now researchers from Chinese Academy of Sciences discovered that a unique disulfide bond-stabilized W1 β4-β1 loop in α₄ β-propeller domain is central to supporting the rolling lymphocyte adhesion and regulating integrin α₄β₇ signaling.

 

Lymphocytes in blood must undergo two critical adhesion stages, rolling and firm adhesion on blood vassal wall before translocating to the target sites. Different from most integrin family members that only mediate firm cell adhesion upon activation, α₄β₇ is able to support rolling and firm lymphocyte adhesion pre- and post-activation respectively, making it indispensable in maintaining the healthy gut immunity. By examining the crystal structure and sequence alignment of integrin α₄β₇ headpiece, Dr. YUE Jiao, Dr PAN Youdong and their colleagues led by Professor CHEN Jianfeng from Shanghai Institute of Biochemistry and Cell Biology, CAS found that the W1 β4-β1 loop exists exclusively in α4/α9 subfamily and is stabilized by a disulfide bond. Either breaking the disulfide bond or deleting the disulfide bond-occluded segment in W1 β4-β1 loop inhibited rolling cell adhesion supported by the inactive α₄β₇, but not the firm cell adhesion mediated by highly activated α₄β₇. Additionally, the disulfide bond-stabilized W1 β4-β1 loop is also pivotal for integrin mediated-bidirectional signaling across the plasma membrane.

 

This work entitled “The unique disulfide bond-stabilized W1 β4-β1 loop in α₄β-propeller domain regulates integrin α₄β₇affinity and signaling” was published online in the Journal of Biological Chemistry on April 3^rd, 2013. It is funded by grants from the Ministry of Science and Technology of China, the National Natural Science Foundation of China, Chinese Academy of Sciences, and the Science and Technology Commission of Shanghai Municipality.

 

Crystal structure of α4β7 headpiece (PDB #3V4P). The disulfide bond-occluded segment in the W1 β4-β1 loop is highlighted in red. (Image by Prof. CHEN Jianfeng)