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Interplay of Intrinsic and Extrinsic Effects of N-glycans on Glycoproteostasis

Award Number: R01DK106582
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: 07/27/2015
PERIOD OF PERFORMANCE END DATE: 06/30/2019

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Interplay of Intrinsic and Extrinsic Effects of N-glycans on Glycoproteostasis - ¿ DESCRIPTION (provided by applicant): About one-third of the proteome of eukaryotes traverses the cellular secretory pathway, and the majority of these proteins are N-glycosylated. Within the secretory pathway there is an elaborate network of chaperones, folding enzymes, and degradation machinery dedicated to maintaining glycoprotein homoeostasis, or "glycoproteostasis". Failures of glycoproteostasis, either because of mutations in N-glycoproteins themselves or defects in the glycoproteostasis network, are responsible for many diseases, including cystic fibrosis. N-glycans affect glycoproteostasis through intrinsic mechanisms, by directly stabilizing glycoproteins and/or inhibiting their aggregation, and through extrinsic mechanisms, by mediating their interactions with the glycoproteostasis network. We have considerable experience studying the extrinsic role of N-glycans in glycoproteostasis maintenance through our studies of the folding and trafficking of glycoproteins associated with lysosomal storage diseases. We have also investigated in depth the intrinsic effects of N-glycans on protein folding and have carefully studied the effects of local sequence on the efficiency of protein N-glycosylation, and their influence on the N-glycan structures produced. In this proposal, we will fuse these areas of expertise to study how N- glycans intrinsically and extrinsically affect folding and trafficking vs. degradation decisions by the glycoproteostasis network. In Specific Aim 1, we will examine how the initial N-glycosylation event by oligosaccharyl transferase (OST) influences downstream trafficking vs. degradation (i.e., quality control) decisions by the glycoproteostasis network. We will explore the effect of N- glycosylation by OSTSTT3A vs. OSTSTT3B (where STT3A and STT3B are the two paralogs of the catalytic subunit of OST) on folding and trafficking vs. degradation decisions, by determining the effect of co-translational folding on substrate selectivity by OSTSTT3A vs OSTSTT3B, and by characterizing the interactomes of nascent glycoproteins and the various isoforms of OST itself. In Specific Aim 2, we will determine how the conformational properties of the N-glycoprotein determine the processing of N-glycans by glycoproteostasis network components. Many components of the glycoproteostasis network bind to N-glycoproteins in a bidentate fashion, interacting with both the N-glycan and the protein. This binding mode enables them to sense both the folding status of the protein and the mode and extent of N-glycan trimming, but it is unclear to what extent this sensing is a function of the immediate protein neighborhood of the N- glycan (neighborhood-local), the entire domain to which the N-glycan is attached (domain-local), or the domains that are remote from the N-glycosylation site (non-local).


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: 2019 ( Subtotal = $0 )
2019	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	9/5/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $433,125 )
2018	2018	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	4	6/18/2018	NON-COMPETING CONTINUATION	$433,125
														Subtotal = $433,125

Issue Date FY: 2017 ( Subtotal = $433,125 )
2017	2017	SCRIPPS RESEARCH INSTITUTE, THE	10550 NORTH TORREY PINES RD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	3	6/30/2017	NON-COMPETING CONTINUATION	$433,125
														Subtotal = $433,125

Issue Date FY: 2016 ( Subtotal = $438,188 )
2016	2016	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	001	2	7/1/2016	NON-COMPETING CONTINUATION	$433,125
2016	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	3/29/2016	NEW	$5,063
														Subtotal = $438,188

Issue Date FY: 2015 ( Subtotal = $426,375 )
2015	2015	SCRIPPS RESEARCH INSTITUTE	10666 NORTH TORREY PINES ROAD	LA JOLLA	CA	92037	SAN DIEGO	USA	Diabetes, Digestive, and Kidney Diseases Extramural Research	000	1	7/27/2015	NEW	$426,375
														Subtotal = $426,375

Grand Total All Awards = $1,730,813

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Interplay of Intrinsic and Extrinsic Effects of N-glycans on Glycoproteostasis

Award Number: R01DK106582

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: 07/27/2015

PERIOD OF PERFORMANCE END DATE: 06/30/2019

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