University of Turku
Supervisor: Jyrki Heino
Integrins are cell surface adhesion molecules that bind to extracellular matrix proteins, such as collagen, and to other cells. Integrins literally integrate extracellular matrix to cytoskeleton and transmit outside-in signals as well as inside-out signals to regulate multiple cellular processes such as cell growth and motility. Integrins lack enzymatic activity, instead signals are transmitted through integrin clustering and conformational changes in integrin structure. Proteins bound to integrin cytoplasmic tails form focal adhesion complexes that are responsible for signal transmission in cytoplasm.
Echovirus 1, small, non-enveloped RNA virus, binds α2β1 integrins to attach cell surface and enter cells. Integrins are internalized from cell membrane in different cell processes and this natural internalization mechanism of integrins might be exploited by virus. In our recent publication (Jokinen et al., 2009) we showed that unlike any other known integrin ligand, echovirus 1 binds better to bent, inactive integrins. Usually integrins bind their ligands more avidly in extended, active conformation. Echovirus 1 has multiple integrin binding sites, and virus binding induces integrin clustering. Integrin conformational changes however do not seem to occur after Echovirus 1 binding.
This PhD project focuses on studying echovirus 1 internalization, but in addition α2β1 integrin signaling related to conformational changes in integrin structure is going to be better understood. Echovirus 1-α2β1 integrin complex is going to be modeled to help to predict interactions between proteins bound to integrin cytoplasmic tails. The composition of this echovirus 1 induced focal adhesion, and signaling through the complex, is going to be defined. Also the role of FAK1, a key protein in focal adhesion regulation, in echovirus 1 entry is going to be determined.