Abstract
The protein kindlin 3 is mutated in the leukocyte adhesion deficiency III (LAD-III) disorder, leading to widespread infection due to the failure of leukocytes to migrate into infected tissue sites. To gain understanding of how kindlin 3 controls leukocyte function, we have focused on its pleckstrin homology (PH) domain and find that deletion of this domain eliminates the ability of kindlin 3 to participate in adhesion and migration of B cells mediated by the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1). PH domains are often involved in membrane localization of proteins through binding to phosphoinositides. We show that the kindlin 3 PH domain has binding affinity for phosphoinositide PI(3,4,5)P3 over PI(4,5)P2. It has a major role in membrane association of kindlin 3 that is enhanced by the binding of LFA-1 to intercellular adhesion molecule 1 (ICAM-1). A splice variant, kindlin 3-IPRR, has a four-residue insert in the PH domain at a critical site that influences phosphoinositide binding by enhancing binding to PI(4,5)P2 as well as by binding to PI(3,4,5)P3. However kindlin 3-IPRR is unable to restore the ability of LAD-III B cells to adhere to and migrate on LFA-1 ligand ICAM-1, potentially by altering the dynamics or PI specificity of binding to the membrane. Thus, the correct functioning of the kindlin 3 PH domain is central to the role that kindlin 3 performs in guiding lymphocyte adhesion and motility behavior, which in turn is required for a successful immune response.
Highlights
Kindlin 3 is mutated in leukocyte adhesion deficiency III (LAD-III) causing widespread infection, but its role in leukocyte function is incompletely understood
To gain understanding of how kindlin 3 controls leukocyte function, we have focused on its pleckstrin homology (PH) domain and find that deletion of this domain eliminates the ability of kindlin 3 to participate in adhesion and migration of B lymphoblastoid cells (B cells) mediated by the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1)
In this study we have examined the role of kindlin 3 PH domain in the activity of the leukocyte integrin LFA-1 on B cells
Summary
Kindlin 3 is mutated in LAD-III causing widespread infection, but its role in leukocyte function is incompletely understood. To gain understanding of how kindlin 3 controls leukocyte function, we have focused on its pleckstrin homology (PH) domain and find that deletion of this domain eliminates the ability of kindlin 3 to participate in adhesion and migration of B cells mediated by the leukocyte integrin lymphocyte function-associated antigen 1 (LFA-1). These positively charged “patches” are aligned along one surface of the H domain, allowing interaction with membrane phosphoinositides (PI) Such extended contact optimally angles the talin H F3 subdomain for interaction with the  subunit favoring integrin ␣ subunit separation. In this study we have examined the role of kindlin 3 PH domain in the activity of the leukocyte integrin LFA-1 on B cells We find that it binds PI[3,4,5]P3 and contributes to the association of kindlin 3 with the B cell membrane. An intact PH domain is required for LFA-1-mediated adhesion and migration on its ligand ICAM-1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
