Thursday, October 24, 2013
Spalding Laboratory 106 (Hartley Memorial Seminar Room)
Chemical Engineering Seminar
Structure and translocation in Nuclear Pore Complexes
Igal Szleifer, Christina Enroth-Cugell Professor of Biomedical Engineering, Biomedical Engineering, Northwestern University
In eukaryotic cells, Nuclear Pore Complexes (NPC) control the transport of species between the cytoplasm and the nucleus using disordered proteins as gate keepers. In this talk I will describe the molecular structure of yeast Nuclear Pore Complex and the translocation of model particles as predicted with a molecular theory that accounts for the geometry of the pore and the amino acid sequence and anchoring position of the unfolded domains of the nucleoporin proteins (the FG-Nups). The theory explicitly models the electrostatic, hydrophobic, steric, conformational and acid-base properties of the FG-Nups. The electrostatic potential within the pore, which arises from the specific charge distribution of the FG-Nups, is predicted to be negative close to pore walls and positive along pore axis. The positive electrostatic potential facilitates the translocation of negatively charged particles and the free energy barrier for translocation decreases for increasing particle hydrophobicity. The above results agree with the experimental observation that transport receptors which form complexes with hydrophilic/neutral or positively charged proteins to transport them through the NPC, are both hydrophobic and strongly negatively charged. The molecular theory shows that the effects of electrostatic and hydrophobic interactions on the translocating potential are cooperative and non-equivalent due to the interaction-dependent reorganization of the FG-Nups in the presence of the translocating particle. The combination of electrostatic and hydrophobic interactions can give rise to complex translocation potentials displaying a combination of wells and barriers, in contrast to the simple barrier potential observed for a hydrophilic/neutral translocating particle. Finally, we will show the importance of explicitly considering the amino acid sequence on the translocation potential. Our studies emphasize the importance of considering protein sequence and hydrophobic, electrostatic and steric interactions in understanding the translocation through the NPC.