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Mallosteric Regulation of the Sterol Pathway

Award Number: R01DK051996
ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/1997
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Mallosteric Regulation of the Sterol Pathway - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $0 )
2026	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	11/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $379,200 )
2024	2024	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	28	7/23/2024	NON-COMPETING CONTINUATION	$379,200
														Subtotal = $379,200

Issue Date FY: 2023 ( Subtotal = $395,000 )
2023	2023	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	27	7/26/2023	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2022 ( Subtotal = $395,000 )
2022	2022	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	26	8/9/2022	NON-COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2021 ( Subtotal = $395,000 )
2021	2021	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	25	9/5/2021	COMPETING CONTINUATION	$395,000
														Subtotal = $395,000

Issue Date FY: 2011 ( Subtotal = $295,580 )
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	15	2/17/2011	NON-COMPETING CONTINUATION	$268,708
2011	2011	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	15	5/27/2011	NON-COMPETING CONTINUATION	$26,872
														Subtotal = $295,580

Issue Date FY: 2010 ( Subtotal = $496,185 )
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	002	13	3/5/2010	SUPPLEMENT FOR EXPANSION	$100,000
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	14	2/4/2010	NON-COMPETING CONTINUATION	$299,338
2010	2010	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Trans-NIH Recovery Act Research Support	000	13	12/21/2009	SUPPLEMENT FOR EXPANSION	$96,847
														Subtotal = $496,185

Issue Date FY: 2009 ( Subtotal = $303,102 )
2009	2009	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	13	1/15/2009	NON-COMPETING CONTINUATION	$272,792
2009	2009	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	13	3/20/2009	NON-COMPETING CONTINUATION	$30,310
														Subtotal = $303,102

Issue Date FY: 2008 ( Subtotal = $303,808 )
2008	2008	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	12	2/4/2008	NON-COMPETING CONTINUATION	$303,808
														Subtotal = $303,808

Issue Date FY: 2007 ( Subtotal = $310,699 )
2007	2007	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	11	1/16/2007	COMPETING CONTINUATION	$310,699
														Subtotal = $310,699

Issue Date FY: 2006 ( Subtotal = $300,938 )
2006	2006	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	10	1/26/2006	NON-COMPETING CONTINUATION	$300,938
														Subtotal = $300,938

Issue Date FY: 2005 ( Subtotal = $334,185 )
2005	2005	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	9	12/17/2004	NON-COMPETING CONTINUATION	$281,440
2005	2005	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	9	1/24/2005	SUPPLEMENT FOR EXPANSION	$52,745
														Subtotal = $334,185

Issue Date FY: 2004 ( Subtotal = $307,435 )
2004	2004	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	8	11/28/2003	NON-COMPETING CONTINUATION	$281,646
2004	2004	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	8	5/27/2004	SUPPLEMENT FOR EXPANSION	$25,789
														Subtotal = $307,435

Issue Date FY: 2003 ( Subtotal = $281,841 )
2003	2003	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	7		NON-COMPETING CONTINUATION	$281,841
														Subtotal = $281,841

Issue Date FY: 2002 ( Subtotal = $286,026 )
2002	2002	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	6	1/14/2002	COMPETING CONTINUATION	$286,026
														Subtotal = $286,026

Issue Date FY: 2001 ( Subtotal = $225,987 )
2001	2001	UNIVERSITY OF CALIFORNIA-SAN DIEGO	Q027	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	5	1/1/2001	NON-COMPETING CONTINUATION	$225,987
														Subtotal = $225,987

Issue Date FY: 2000 ( Subtotal = $219,548 )
2000	2000	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	12/20/1999	NON-COMPETING CONTINUATION	$219,548
														Subtotal = $219,548

Issue Date FY: 1999 ( Subtotal = $213,299 )
1999	1999	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	2/6/1999	NON-COMPETING CONTINUATION	$213,299
														Subtotal = $213,299

Issue Date FY: 1998 ( Subtotal = $207,235 )
1998	1998	UNIVERSITY OF CALIFORNIA-SAN DIEGO	9500 GILMAN DRIVE	LA JOLLA	CA	92093	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	2	12/23/1997	NON-COMPETING CONTINUATION	$207,235
														Subtotal = $207,235

Grand Total All Awards = $5,650,068

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Mallosteric Regulation of the Sterol Pathway

Award Number: R01DK051996

ORGANIZATION: NATIONAL INSTITUTE OF DIABETES & DIGESTIVE & KIDNEY DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 01/01/1997

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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