# A solid state conceptualization of information transfer from gene to message to protein

> **NIH NIH R35** · UT SOUTHWESTERN MEDICAL CENTER · 2024 · $533,000

## Abstract

Project Summary/Abstract:
Normal proteins utilize most or all of life’s 20 amino acids to fold into stable structures responsible for their biological
function. Perplexingly, between 10 and 20% of the proteins found in eukaryotic cells are unusual in containing only a
subset of the 20 amino acid residues utilized by normal proteins. These unusual proteins are described as being of low
sequence complexity and have long been understood to exist in states of intrinsic disorder. Despite constituting no more
than 20% of the proteome, upwards of 75% of all forms of post-translational modification have been mapped to low
complexity (LC) domains. It is likewise the case than more than 50% of all forms of alternative pre-mRNA splicing map to
LC domains. These facts predict that a disproportionate amount of cellular regulation funnels through LC domains.
More than a decade ago the group led by Dirk Gorlich at the Max Planck Institute for Biophysical Chemistry in Munich,
Germany described the surprising ability of a low complexity domain to become phase separated in the form of a
hydrogel. The work of Gorlich and colleagues was focused on the phenylalanine:glycine-rich low complexity (LC) domains
of nucleoporin proteins, and their work offered a conceptual framework for understanding how the permeability barrier
of the nuclear pore might work in a mechanistic sense. Parallel work by the McKnight lab in the Biochemistry
Department of UT Southwestern Medical Center yielded similar findings in studies of the tyrosine:glycine-rich LC domain
of the fused-in-sarcoma (FUS) RNA binding protein. In the latter case, self-association by the FUS LC domain was
postulated to represent the basis by which RNA-rich membraneless granules form in the cytoplasm of eukaryotic cells.
Over the past decade the McKnight laboratory investigated the concept that self-association of LC domains is mediated
by the formation of labile cross-β structures poised at the threshold of thermodynamic equilibrium. In collaborative
experiments with Robert Tycko at the National Institutes of Health, the McKnight group described the first atomic
structure of a labile cross-β structure. This work revealed the chemical basis accounting for both the lability of the FUS
structure and the specificity of self-association. It also showed that the structure was invariantly formed from the same,
limited segment of the FUS LC domain. The structure-forming region of the FUS LC domain has come to be termed a
labile, cross-β core. Similarly labile and invariantly localized cross-β cores have now been discovered within the LC
domains of three other RNA binding proteins (hnRNPA2, TDP-43 and ataxin-2), the phenylalanine:glycine repeats of the
Nup54 and Nup98 nucleoporin proteins, and the LC domains localized within the amino terminal segments of six different
intermediate filament proteins. Extensive evidence has established that cross-β cores nucleate self-association, phase
separation and the biological function...

## Key facts

- **NIH application ID:** 10763771
- **Project number:** 2R35GM130358-06
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** STEVEN L MCKNIGHT
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $533,000
- **Award type:** 2
- **Project period:** 2019-02-01 → 2029-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10763771

## Citation

> US National Institutes of Health, RePORTER application 10763771, A solid state conceptualization of information transfer from gene to message to protein (2R35GM130358-06). Retrieved via AI Analytics 2026-06-11 from https://api.ai-analytics.org/grant/nih/10763771. Licensed CC0.

---

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