# Decoding the structures and lipid binding specificity of small GTPase membrane anchors

> **NIH NIH R01** · UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON · 2020 · $335,720

## Abstract

PROJECT SUMMARY
We recently discovered that the polybasic domain (PDB) of the K-Ras membrane anchor adopts defined
dynamic structures on the PM that allow for highly selective interactions with membrane lipids. We also found
that PBDs with different primary sequences have the capacity to encode different lipid binding specificities.
Thus interactions of PBDs with the plasma membrane (PM) are considerably more complex than simple
electrostatics. Further analysis showed that the lipid binding specificity of the K-Ras anchor is a key
determinant of signal output. In parallel we made the intriguing discovery that PM potential selectively
modulates the diffusional dynamics and spatial organization of specific negatively charged lipids and thereby
regulates the extent of K-Ras nanoclustering and signaling. This novel mechanism whereby electrical signals
can modulate classical signaling pathways through protein-lipid interactions is the basis of electrical regulation
of lipid based signaling platforms. In this new grant we will build on these exciting preliminary observations to
further define the molecular details of K-Ras membrane anchor structure and function and study the structural
dynamics of other small GTPases on the PM. Our core hypothesis is that the observations we have made with
K-Ras are generalizable to other small GTPases that have a PBD-containing membrane anchor. Thus in Aim 1
we will test the hypothesis that the K-Ras PM anchor is substantially more complex than a passive charge
detector using a wide-range of experimental techniques and molecular simulations. We will show that PBD
sequence and conformational dynamics generate lipid-binding specificity that is critical for function. We will test
the generalizability of this hypothesis in Aim 2 by analyzing other members of the Ras superfamily. We will also
define the PM spatial organization of the same set of proteins. Aim 3 will investigate the molecular
mechanisms and the dependence of membrane interactions of multiple small GTPases on membrane
potential. The results will yield new insights into how lipid-binding specificity is encoded in the membrane
anchors of small GTPases to render them subject to PM lipid composition and organization. Since small
GTPases regulate many aspects of cell biology and their dysfunction is linked to multiple pathologies, including
oncogenesis, the results will have wide-ranging implications.

## Key facts

- **NIH application ID:** 9897543
- **Project number:** 5R01GM124233-03
- **Recipient organization:** UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
- **Principal Investigator:** Alemayehu A. Gorfe
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $335,720
- **Award type:** 5
- **Project period:** 2018-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9897543

## Citation

> US National Institutes of Health, RePORTER application 9897543, Decoding the structures and lipid binding specificity of small GTPase membrane anchors (5R01GM124233-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9897543. Licensed CC0.

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