# Intrinsically disordered proteins as physical drivers of membrane traffic

> **NIH NIH R01** · UNIVERSITY OF TEXAS AT AUSTIN · 2020 · $300,163

## Abstract

PROJECT SUMMARY Membrane traffic, an essential cellular process that plays a role in many human
diseases, requires key biophysical steps including formation of membrane buds, loading of these buds with
specific molecular cargo, separation from the parent membrane, and fusion with the target membrane. The
prevailing view has been that structured protein motifs drive these processes. However, many proteins that
contain these structural motifs also contain large intrinsically disordered protein (IDP) domains of 300-1500
amino acids, including most clathrin adaptor proteins and COPII coat components. While these IDP domains
have been regarded primarily as flexible binding and recruitment motifs, the principal investigator's laboratory
has recently reported that IDPs are highly efficient drivers of membrane remodeling in their own right. Further,
preliminary data for the proposed work demonstrate that when IDP domains bind membrane surfaces in
sufficient numbers, they serve as strong drivers of membrane fission. How can molecules without a defined
structure drive membrane bending and fission? Substantial preliminary data in this application supports the
working hypothesis that disordered domains are highly effective drivers of membrane remodeling through the
mechanism of protein crowding. Specifically, the work of the principal investigator, supported by findings from
others, has recently revealed that collisions among membrane-bound proteins generate entropic pressure that
provides a potent driving force for membrane deformation. IDPs are particularly efficient generators of entropic
pressure owing to their large hydrodynamic radii and the substantial energetic cost of extending them. Building
on preliminary findings, the goal of the proposed work is to elucidate the physical roles of IDPs in membrane
traffic by measuring the impact of entropic pressure on key steps of the process. Work in Aim 1 will elucidate
the physical mechanisms that IDPs use to generate entropic pressure, testing the working hypothesis that it
depends on steric, electrostatic, and lipid-mediated interactions. Work in Aim 2 will measure the contribution of
IDPs to membrane fission, testing the working hypothesis that IDP domains generate entropic pressure that
dramatically reduces the energetic cost of membrane fission. Finally, work in Aim 3 will use disordered
polymers to assess and control receptor selection by trafficking vesicles, testing the working hypothesis that
entropic pressure among bulky receptors opposes endocytic uptake and can be used as a tool to drive
accumulation of receptors at the plasma membrane. The significance of this work lies in its potential to change
how we think about the molecules and mechanisms that control membrane traffic. Specifically, while current
models focus on specific structural domains thought to sculpt membrane surfaces, this work suggests that
proteins that lack defined structure, IDPs, may be among the most potent drivers of membrane ...

## Key facts

- **NIH application ID:** 9853806
- **Project number:** 5R01GM120549-04
- **Recipient organization:** UNIVERSITY OF TEXAS AT AUSTIN
- **Principal Investigator:** Jeanne Casstevens Stachowiak
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $300,163
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9853806

## Citation

> US National Institutes of Health, RePORTER application 9853806, Intrinsically disordered proteins as physical drivers of membrane traffic (5R01GM120549-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9853806. Licensed CC0.

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