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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Cohen, Edward H. Peer, Dan Ferrand, Audrey Springer, Timothy A. Kim, Minsoo Salas, Azucena Shimaoka, Motomu Astrof, Nathan Yang, Wei |
| Description | Author Affiliation: Shimaoka M ( CBR Institute for Biomedical Research and Department of Anesthesia, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA. shimaoka@cbrinstitute.org); |
| Abstract | Affinity of integrin lymphocyte function-associated antigen 1 (LFA-1) is enhanced by conformational changes from the low-affinity closed form to the high-affinity (HA) open form of the ligand-binding inserted (I) domain as shown by work with purified I domains. However, affinity up-regulation of LFA-1 on the cell surface by physiological agonists such as chemokines has yet to be demonstrated by monovalent reagents. We characterize a mAb, AL-57 (activated LFA-1 clone 57), that has been developed by phage display that selectively targets the HA open conformation of the LFA-1 I domain. AL-57 discriminates among low-affinity, intermediate-affinity, and HA states of LFA-1. Furthermore, AL-57 functions as a ligand mimetic that binds only upon activation and requires Mg2+ for binding. Compared with the natural ligand intercellular adhesion molecule-1, AL-57 shows a tighter binding to the open I domain and a 250-fold slower off rate. Monovalent Fab AL-57 demonstrates affinity increases on a subset (approximately 10%) of lymphocyte cell surface LFA-1 molecules upon stimulation with CXCL-12 (CXC chemokine ligand 12). Affinity up-regulation correlates with global conformational changes of LFA-1 to the extended form. Affinity increase stimulated by CXCL-12 is transient and peaks 2 to 5 min after stimulation. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 38 |
| Volume Number | 103 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2006-09-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Antibodies, Monoclonal Metabolism Antibody Affinity Chemokines, CXC Lymphocyte Function-Associated Antigen-1 Lymphocytes Amino Acid Sequence Animals Genetics Binding Sites Cell Line Chemokine CXCL12 Epitopes Ligands Chemistry Molecular Sequence Data Protein Binding Protein Structure, Tertiary Surface Plasmon Resonance Up-Regulation Research Support, N.I.H., Extramural Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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