Date of Award
Cell adhesion molecules, Cytoskeletal proteins, Integrins, Integrins -- Structure-activity relationships, Biochemistry, Kindlin2, Migfilin, Integrin, Integrin activation
Kindlins are a novel family of cytoskeleton proteins that plays an important role in the activation of heterodimeric integrin transmembrane receptors. These receptors play a vital role in cell adhesion, cell migration and other cellular processes. The Kindlin protein family consists of three homologous proteins, Kindlin 1, 2 and 3 with differential tissue distribution and varying expression levels in human. Mutations of Kindlin 1 protein are clinically linked to Kindler Syndrome. Kindlin 2 knockdown studies have shown embryonic lethality in mouse, but no diseases have been clinically testified. Kindlin 3 mutations are associated with bleeding disorders, e.g. LADIII. Talin is a cytoskeleton protein, which is a well known and widely studied activator of integrin receptors. Talin and Kindlin bind to non-overlapping binding sites on integrin ├ƒ3 cytoplasmic tail. Their cooperation significantly enhances integrin activation compared to integrin activation by Talin activity itself. Kindlin and Talin share similar structural homology. A unique feature in the Kindlin FERM domain compared to the FERM domain of Talin is that the FERM domain of Kindlin is split by a PH domain. The main focus of the study was to understand the role of Kindlin 2 in the complex process of integrin activation. To gain structural insight, we have determined the 3D structure of Kindlin 2 N-terminal F0 domain by using Nuclear Magnetic Resonance Spectroscopy. More than 90 of the backbone and side chain NMR resonances have been assigned. Kindlin 1 and 2 F0 domains share 62 sequence homology and have a similar ubiquitin-like beta grasp fold. However, there are distinct differences between Kindlin 1 and 2 F0 domain structures, which may contribute to functional differences. An in vivo assay has shown that deletion of the F0 domain from the Kindlin 2 full length protein abolishes integrin activation. Thus, Kindlin 2 F0 domain plays a significant role in integrin activation. Our in vitro data have shown a very weak interaction between Kindlin 2 F0
Perera, Hettiarachchige Dhanuja deepamalee, "Molecular Basis of the Role of Kindlin 2 in Cell Adhesion" (2010). ETD Archive. 236.