The Structure and Function of αI Domains in Collagen Receptor and Leukocyte Integrins

4 Matti Lahti (2012) The structure and function of I domains in collagen receptor and leukocyte integrins. Department of Biochemistry and Food Chemistry, and Turku Doctoral Programme of Biomedical Sciences, University of Turku, Turku, Finland. Annales Universitatis Turkuensis, Series A1, 453. ABSTRACT Integrins are heterodimeric, signaling transmembrane adhesion receptors that connect the intracellular actin microfilaments to the extracellular matrix composed of collagens and other matrix molecules. Bidirectional signaling is mediated via drastic conformational changes in integrins. These changes also occur in the integrin I domains, which are responsible for ligand binding by collagen receptor and leukocyte specific integrins. Like intact integrins, soluble I domains exist in the closed, low affinity form and in the open, high affinity form, and so it is possible to use isolated I domains to study the factors and mechanisms involved in integrin activation/deactivation. Integrins are found in all mammalian tissues and cells, where they play crucial roles in growth, migration, defense mechanisms and apoptosis. Integrins are involved in many human diseases, such as inflammatory, cardiovascular and metastatic diseases, and so plenty of effort has been invested into developing integrin specific drugs.Integrins are heterodimeric, signaling transmembrane adhesion receptors that connect the intracellular actin microfilaments to the extracellular matrix composed of collagens and other matrix molecules. Bidirectional signaling is mediated via drastic conformational changes in integrins. These changes also occur in the integrin I domains, which are responsible for ligand binding by collagen receptor and leukocyte specific integrins. Like intact integrins, soluble I domains exist in the closed, low affinity form and in the open, high affinity form, and so it is possible to use isolated I domains to study the factors and mechanisms involved in integrin activation/deactivation. Integrins are found in all mammalian tissues and cells, where they play crucial roles in growth, migration, defense mechanisms and apoptosis. Integrins are involved in many human diseases, such as inflammatory, cardiovascular and metastatic diseases, and so plenty of effort has been invested into developing integrin specific drugs. Humans have 24 different integrins, four of which are collagen receptor (11, 21, 101, 111) and five leukocyte specific integrins (L2, M2, X2, D2, E7). These two integrin groups are quite unselective having both primary and secondary ligands. This work presents the first systematic studies performed on these integrin groups to find out how integrin activation affects ligand binding and selectivity. These kinds of studies are important not only for understanding the partially overlapping functions of integrins, but also for drug development. In general, our results indicated that selectivity in ligand recognition is greatly reduced upon integrin activation. Interestingly, in some cases the ligand binding properties of integrins have been shown to be cell type specific. The reason for this is not known, but our observations suggest that cell types with a higher integrin activation state have lower ligand selectivity, and vice versa. Furthermore, we solved the three-dimensional structure for the activated form of the collagen receptor α1I domain. This structure revealed a novel intermediate conformation not previously seen with any other integrin αI domain. This is the first 3D structure for an activated collagen receptor αI domain without ligand. Based on the differences between the open and closed conformation of the I domain we set structural criteria for a search for effective collagen receptor drugs. By docking a large number of molecules into the closed conformation of the 2I domain we discovered two polyketides, which best fulfilled the set structural criteria, and by cell adhesion studies we showed them to be specific inhibitors of the collagen receptor integrins.