# Structure-Function Mapping of the Nuclear Pore Complex-Renewal

> **NIH NIH R01** · ROCKEFELLER UNIVERSITY · 2024 · $668,760

## Abstract

ABSTRACT
Nuclear pore complexes (NPCs) are huge macromolecular assemblies that serve as the only conduit for
bidirectional transport between the nucleus and cytoplasm. We have determined the constituents, architecture,
and detailed high precision structure of the archetypal yeast NPC. However, despite our increasing structural
information on NPCs, we still lack a fundamental understanding of the mechanics of numerous of its functions.
With our detailed maps in hand, we are, for the first time, in a unique position to map and reveal the structural
changes associated with functional states that throw light on mechanisms underlying critical aspects of NPC
function. Our hypothesis is that, despite some overlap, discrete and distinct structural stages and states are
associated with NPCs’ varied functions. We have therefore established a powerful pipeline for analyzing NPCs
and their vicinal associated complexes both structurally and functionally in defined functional states onto which
we map quantitative phenotypic information. This information will allow us to move from static models of NPCs
to working models of the machine in action, breathing life into our NPC maps and dissecting out how particular
functionalities are mechanistically supported at the structural level. We focus on two such functionalities that are
central to nuclear function at two related levels: first, as a regulator of transport, NPCs control mRNA packaging
and export to the cytoplasm to both mediate and regulate gene expression; and second, NPCs directly control
genes by binding chromatin and its regulators to alter expression states epigenetically. Both processes are
incompletely understood at the molecular level, and have profound effects on cellular function as evidenced by
the fact that disruptions of NPC-associated proteins associated with these functions lead to many human
diseases. For Aim 1, we will determine the molecular machinery of NPC-mediated mRNP export by studying
NPCs effectively “frozen” in defined intermediate stages of mRNP export. For Aim 2, we will determine the
molecular machinery of NPC-mediated chromatin organization, specifically focusing on subtelomeric gene
silencing. Using our established pipeline, we will identify and structurally characterize these NPC stages and
states and their vicinal interactomes. Realizing these Aims will generate NPC structure-function maps in
unprecedented detail, which will be of great use to the field to understanding how the mRNP export and
chromatin remodeling machineries act in concert with different parts of the NPC to enable their functionalities
and will shed light on the nature of numerous disorders associated with dysfunction in these processes. The
resulting structure-function NPC maps promise to set the stage for tapping the NPC’s tremendous potential as
a drug target for many human conditions ranging from cancers to infectious diseases to developmental and
neurological disorders.
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## Key facts

- **NIH application ID:** 10915468
- **Project number:** 5R01GM112108-10
- **Recipient organization:** ROCKEFELLER UNIVERSITY
- **Principal Investigator:** JOHN D. AITCHISON
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $668,760
- **Award type:** 5
- **Project period:** 2015-03-01 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10915468

## Citation

> US National Institutes of Health, RePORTER application 10915468, Structure-Function Mapping of the Nuclear Pore Complex-Renewal (5R01GM112108-10). Retrieved via AI Analytics 2026-05-29 from https://api.ai-analytics.org/grant/nih/10915468. Licensed CC0.

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