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Deconstructing Nuclear Pore Complex Function by Bio-Synthetic Reconstruction

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If you have a question about this talk, please contact Tracy Inman.

The manner by which specific macromolecules are sorted and transported in the complex environment of living cells (i.e., protein targeting) is unprecedented and unmatched by technology. Yet, how does a molecule get to exactly where it is supposed to in the cell? This defines the driving impetus in our lab to resolve the modus operandi of the nuclear pore complex (NPC), which regulates macromolecular traffic between the nucleus and the cytoplasm.

As a 50 nm-diameter physical pore, the biological marvel of the NPC lies in its ability to restrict or promote cargo translocation via biochemical selectivity and not size exclusion per se. Moreover, unlike synthetic nanopores, the NPC does not clog in vivo – in spite of the molecular complexity of the cellular environment.

Here we use a hybrid methods approach to resolve and correlate across the pertinent biophysical, biochemical and structural aspects of NPC functionality. These efforts range from (i) applying AFM to study the nanomechanical response of the key NPC proteins (i.e., intrinsically disordered phenylalanine-glycine (FG)-rich nucleoporins or FG Nups) on pore-like nanostructures; (ii) to correlating binding-induced conformational changes in the FG Nups to binding affinities using surface plasmon resonance; (iii) to constructing biomimetic nanopores that reproduce the transport selectivity of the NPC .

In my talk, I will describe how these efforts provide new insight into the underlying principles governing molecular mechanics, selectivity and transport in the NPC . By replacing the NPC machinery with synthetic polymers, I will further demonstrate how NPC -like functionality can be harnessed to target specific proteins from authentic biological environments to site-selective locations with nanoscale precision in technological systems.

1. J. T. Hyotyla, J. Deng and R. Y. H. Lim, Synthetic Protein Targeting by the Intrinsic Biorecognition Functionality of Poly(ethylene glycol) using PEG -Antibodies as Biohybrid Molecular Adaptors, ACS Nano, 5 5180 (2011) 2. S. W. Kowalczyk, L. Kapinos, T. Magalhães, P. van Nies, R. Y. H. Lim, and C. Dekker, Single-Molecule Transport Across an Individual Biomimetic Nuclear Pore Complex, Nature Nanotechnology, 6 433 (2011) 3. Peleg O. and Lim R. Y. H., Converging on the Function of Intrinsically Disordered Nucleoporins in the Nuclear Pore Complex, Biological Chemistry 391 719 (2010) 4. R. Y. H. Lim, B. Fahrenkrog, J. Koser, K. Schwarz-Herion, J. Deng, and U. Aebi, Nanomechanical Basis of Selective Gating by the Nuclear Pore Complex, Science, 318 640 (2007) 5. Lim, R. Y. H., Huang, N. P., Koser, J., Deng, J., Lau, K. H. A., Schwarz-Herion, K., Fahrenkrog, B. & Aebi, U. Flexible Phenylalanine-Glycine Nucleoporins as Entropic Barriers to Nucleocytoplasmic Transport, PNAS 103 , 9512 (2006)

This talk is part of the BSS Formal Seminars series.

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