Project Details
Description
PARENT AWARD ABSTRACT
The sole mediators of nucleocytoplasmic transport of macromolecules are Nuclear Pore Complexes
(NPCs), comprised of proteins termed nucleoporins (Nups). The specific mechanism by which these
nucleoporins provide selective diffusion of nuclear transport factor (NTR)-linked cargoes is
hypothesized to involve relatively weak interactions between transport factors and phenylalanyl glycyl
rich (FG) repeat regions found in certain Nups (FG-Nups) to provide selectivity, while the continuous
high degree of FG-repeat region dynamic disorder provides sufficient speed to the process, aiding
selective diffusion. Defects in nuclear transport and the NPC are associated with numerous
diseases, making them an important therapeutic target that is still underuseddue to our poor
mechanistic understanding of transport. In this continuation, we seek to:(i) understand the
complexities of this mechanism with various FG-Nups (with different ‘flavors’ of FGs) and different
nuclear transport factors (NTRs); ii) establish the underlying properties associated with potential
different mechanistic routes for NTRs, and how NTRs and non-transported biomolecules are
discriminated in the NPC; and iii) pioneer how to understand the nanoscale ensemble structures of
the components. Our integrative studies using protein engineering, NMR, SANS, as well as other
biophysical methods and molecular dynamics (MD) simulation to provide paradigmatic tools validated
for an IDP system with a well-defined (if unusual) function. Our goals are therefore to dissect at
atomic resolution how FG repeat regions in the NPC selectively restrict diffusion of non-specific
macromolecules while permitting the efficient exchange of NTRs, using three synergistic but non-
overlapping Aims: (1) determine the specificities of interactions of different FG-repeat flavors and
NTR types; (2) determine the ensemble structures of FG repeats and how they are altered on
interaction with NTRs; and (3) determine how different NTRs move in the presence of ensembles of
different FG repeat flavors.
The outcome of this research will be the first atomic scale dynamic pictures of the functional roles of
FG repeatregions by describing for the two major flavors of FG repeats contributing to most of the
flux in the NPC. This isat three levels: i) themes and variations in the interaction of different FG repeat
types with different NTRs; ii) underlying polymer properties of different FG repeat types; iii) how the
actual enhancement of relative diffusionof NTRs compared to other similar materials comes about.
The impact of this research will be a substantial increase in our knowledge of the detailed
mechanisms of nuclear transport. These data will enable a route to future translational efforts to
modify nuclear transport where it has been adversely affected in diseased cells.
Status | Active |
---|---|
Effective start/end date | 3/1/16 → 7/31/24 |
Funding
- National Institute of General Medical Sciences: $422,297.00
- National Institute of General Medical Sciences: $405,761.00
- National Institute of General Medical Sciences: $405,761.00
- National Institute of General Medical Sciences: $200,031.00
- National Institute of General Medical Sciences: $500,255.00
- National Institute of General Medical Sciences: $483,505.00
- National Institute of General Medical Sciences: $483,505.00
- National Institute of General Medical Sciences: $405,761.00
- National Institute of General Medical Sciences: $122,679.00
- National Institute of General Medical Sciences: $283,474.00
Fingerprint
Explore the research topics touched on by this project. These labels are generated based on the underlying awards/grants. Together they form a unique fingerprint.