# Mallosteric Regulation of the Sterol Pathway

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA, SAN DIEGO · 2021 · $395,000

## Abstract

HMG-CoA reductase (HMGR) is a key enzyme of the sterol pathway. HMGR undergoes feedback-
regulated degradation conserved from yeast to humans. We exploit this conservation to understand the
machinery and mechanisms at play in regulated degradation of the yeast Hmg2 isozyme. Degradation
occurs by the HRD ER-associated degradation (ERAD) quality control pathway, also responsible for the
degradation of misfolded ER proteins. Hmg2 ERAD is regulated by sterol pathway molecule GGPP.
GGPP accomplishes control by causing reversible misfolding that triggers HRD pathway degradation.
GGPP’s action on Hmg2 has many features of allosteric control; we have named this type of regulation
“mallostery” to combine the ideas of misfolding and allostery. In the proposed studies we will unravel the
mallosteric regulation of Hmg2, to better understand sterol pathway control, and for the high potential
mallostery holds as broadly applicable avenue of drug discovery. Specifically, we will : 1) Study the
features of Hmg2 that allow GGPP-dependent reversible misfolding: GGPP’s effect on the Hmg2
transmembrane regions is highly specific, and requires the broadly conserved sterol sensing domain
(SSD). We will discover the sequence features of Hmg2 responsible for mallosteric control by GGPP,
investigating the role of known Hmg2 motifs and discovering sequence features with unbiased genetic
approaches; 2) Explore the mechanism of GGPP dependent regulation of Hmg2- We will test the
hypothesis that GGPP is a high potency ligand for Hmg2, causing reversible misfolding through
development of direct interaction assays, analysis of GGPP analogues, and through in vitro reconstitution
of regulated ubiquitination of Hmg2 using a number tools and approaches developed in the last funding
cycle; and 3) Discover the role of INSIG proteins in GGPP-mediated misfolding of Hmg2- The INSIG
proteins are critical in mammalian lipid homeostasis, and are conserved in yeast (Nsg1 and 2). As in
mammals, yeast INSIGs function by transducing sterol signals. Yeast INSIG controls GGPP-dependent
Hmg2 misfolding in a manner dependent on the biosynthetic sterol lanosterol. Thus the yeast INSIGs
impose a second layer of regulation on mallosteric regulation by GGPP. We will use the tools, mutants,
and methods from both the previous funding period, and the above studies to explore the mechanism
and physiology INSIG function in Hmg2 regulated stability. We will also execute a genetic screen to glean
the broader biology of INSIGs, about which almost nothing is known despite the key and highly conserved
roles of these proteins in human lipid homeostasis and pathology.

## Key facts

- **NIH application ID:** 10299127
- **Project number:** 2R01DK051996-25
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, SAN DIEGO
- **Principal Investigator:** Randolph Y. Hampton
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $395,000
- **Award type:** 2
- **Project period:** 1997-01-01 → 2025-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10299127

## Citation

> US National Institutes of Health, RePORTER application 10299127, Mallosteric Regulation of the Sterol Pathway (2R01DK051996-25). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10299127. Licensed CC0.

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