# Structure-Function of Nucleo-Cytoplasmic Communication

> **NIH NIH R35** · MASSACHUSETTS INSTITUTE OF TECHNOLOGY · 2022 · $379,880

## Abstract

PROJECT SUMMARY / ABSTRACT
Eukaryotic cells are defined by their organelles, membrane-enclosed compartments in which specific cellular
processes are carried out. The nucleus is the largest organelle, contains all genetic material, and enables
separation of gene transcription from protein translation. As the nuclear envelope (NE) serves as a tight barrier
enclosing the nucleus, the cell requires machinery to establish and control nucleo-cytoplasmic communication.
There are two principally different components to this machinery. On one hand, nuclear pore complexes
(NPCs) serve as the main conduit for molecular exchange across the NE. On the other hand, universally
conserved linker of nucleo- and cytoskeleton (LINC) complexes serve as physical tethers across the NE, which
are necessary for positioning the nucleus and for mechano-sensing in a diverse set of circumstances.
Dysfunction of the machinery is at the core of important human diseases, including skeletal and cardiac
myopathies, premature aging, and cancer. Our goal is to understand the structure of the protein complexes
involved in nucleo-cytoplasmic communication at high (atomic) resolution. Such information helps to identify
and separate the myriad functions this machinery carries out and that we are still only beginning to fully grasp.
High resolution information further provides the basis for structure-guided drug design to interfere with the
salient human diseases, such as Emery-Dreifuss Muscular Dystrophy (EDMD) and Primary Dystonia, which
are still not cured. The structural characterization of the NPC and the LINC complex are challenging, because
of the size and complexity of these multi-MDa assemblies. Over the past 15 years, we have made significant
advances on both problems. For the NPC, we have chosen a highly productive bottom-up approach, in which
we characterized multi-subunit complexes predominantly by X-ray crystallography, the building blocks of the
massive, 40-100 MDa NPC. Those structures have now been used in combination with cryo-electron
tomographic (cryo-ET) maps of assembled NPCs to generate composite structures that attempt to position the
roughly 500 individual proteins within one NPC. For the LINC complex, we solved the universally conserved
core component and have started to untangle the diverse network of its components, the Sad1/UNC-84 (SUN)
and Klarsicht/ANC1/Syne-Homology (KASH) proteins. Going forward, the challenge is the structural
characterization of large and dynamic assemblies, which is true for both, the NPC and the LINC complex, for
the latter particularly when including the connection to the nucleo- and cytoskeletal components. The dramatic
advances in cryo-electron microscopy (cryo-EM) over the recent past make this technology particularly
important for our studies. We anticipate combining X-ray crystallography and cryo-EM for studying the most
relevant structures going forward. The success of this will depend upon innovative, tailored methods to
addr...

## Key facts

- **NIH application ID:** 10475615
- **Project number:** 5R35GM141834-02
- **Recipient organization:** MASSACHUSETTS INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Thomas Schwartz
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $379,880
- **Award type:** 5
- **Project period:** 2021-09-01 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10475615

## Citation

> US National Institutes of Health, RePORTER application 10475615, Structure-Function of Nucleo-Cytoplasmic Communication (5R35GM141834-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10475615. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*