# Biochemical and cellular functions of Karyopherins - Revision - 2

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $11,592

## Abstract

Abstract of grant R35GM141461:
Twenty homologous Karyopherin- (Kap) proteins mediate the majority of protein transport
between the nucleus and the cytoplasm. The Chook Lab is a leader in understanding the
mechanisms by which Kaps control macromolecular traffic. We achieve this understanding
through a combination of structural, biochemical, cell biological and bioinformatic analyses of
Kap-ligand interactions. Our studies of the nuclear import receptor Kapβ2 led to discovery of
the proline-tyrosine nuclear localization signal (PY-NLS), which it recognizes. This study led
to a new concept—that many nuclear targeting signals are defined not merely by sequence
but by a collection of physical features—which explained how Kapβ2 can recognize hundreds
of different sequences, and enabled us to design the first nuclear import inhibitor. Although
two additional NLS types have recently been determined, cargo recognition by most importins,
including Importins-4, -7, -8, -9 and -11 is not understood even though they account for 50%
of nuclear import. Few of their cargos are known and the NLS classes that they recognize are
unknown. The missing knowledge obscures our understanding of how a significant portion of
the proteome lacking recognizable NLSs are trafficked into the nucleus. We aim to discover
new cargos, classes of NLSs and pathway-specific inhibitors for all importins. We will combine
this knowledge with bioinformatic analyses and experiments to define the full cargo repertoires
of each importin, and thus map both the traffic and cellular processes that they each control.
We showed that in addition to mediating nuclear import, importins also act as chaperones.
We will learn how Kap2 chaperones RNA-binding proteins, preventing their aggregation and
understand the functional significance of the Importin-9 histone-chaperone function in histone
storage and nucleosome assembly. In our studies of nuclear export, we were the first to reveal
how CRM1 recognizes the only known nuclear export signal (NES). This work was
foundational for development of the anti-cancer drug Selinexor, and the physical/chemical
mechanisms of inhibition that we later revealed contributed to FDA-approval of the drug. We
also revealed the sequence and structural degeneracy of the NES, explaining how CRM1 is
able to recognize hundreds of diverse NES sequences. CRM1 also exports thousands of
mRNAs, but little is known about the mechanism. We will study CRM1-mRNA export
complexes to shed light on this critical step of gene expression. Finally, we will expand study
to the exportin Msn5, which binds intrinsically disordered and phosphorylated segments of
multiple cargos. This work will reveal a second, new class of NES.

## Key facts

- **NIH application ID:** 11099514
- **Project number:** 3R35GM141461-04S1
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Yuh Min Chook
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $11,592
- **Award type:** 3
- **Project period:** 2021-06-11 → 2026-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11099514

## Citation

> US National Institutes of Health, RePORTER application 11099514, Biochemical and cellular functions of Karyopherins - Revision - 2 (3R35GM141461-04S1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/11099514. Licensed CC0.

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