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Molecular mechanisms of protein glycosylation and trafficking

Award Number: R01CA231466
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/18/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Molecular mechanisms of protein glycosylation and trafficking - Project Summary The objective of this proposal is to gain mechanistic and pathological understanding of protein glycosylation and trafficking. During the previous funding cycle, we have made important contributions to this process. We have determined the structure of the transmembrane domain insertase EMC complex, revealing an elongated cavity in the transmembrane region of the structure that can accommodate a weakly hydrophobic transmembrane helix. We have solved the structures of the protein N-glycosyltransferase (OST) and the protein O-mannosyltransferase Pmt1-Pmt2, revealing the evolutionarily conserved GT-C folds of their catalytic subunits. Protein trafficking requires lipid vesicle formation, a process that is dependent on lipid flippase activity to establish compositional asymmetry between the two leaflets of the bilayer. In this regard, we have determined the structures of all three classes of yeast lipid flippases. This renewal proposal continues our overarching goal to understand protein glycosylation and trafficking. We propose to address two specific knowledge gaps: the structure and mechanism of two protein mannosyltransferases, and how the recently discovered ternary protein complex Arl1-Gea2-Drs2 couples lipid flipping activity with membrane curvature formation, thereby facilitating the downstream vesicle budding process for protein and membrane trafficking. Drs2 is a phosphatidylserine flippase required for the formation of AP-1/clathrin-coated vesicles that travel back and forth between the trans-Golgi network (TGN) and early endosomes. The small GTPase Arl1 is a member of the ADP-ribosylation factor (Arf) family that is activated by the Arf guanine nucleotide exchange factor Gea2. Arl1 operates exclusively in the TGN and is the least well-understood member of the Arf family. We will reconstitute the ternary complex in vitro and perform a comprehensive structure-function study. Protein glycosylation and trafficking is intimately linked to tumorigenesis and cancer progression. Our mechanistic studies will fill these fundamental knowledge gaps, and our derived structures may facilitate the development of small molecules for cancer treatment.


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: 2025 ( Subtotal = $475,000 )
2025	2025	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	8	8/15/2025	NON-COMPETING CONTINUATION	$475,000
														Subtotal = $475,000

Issue Date FY: 2024 ( Subtotal = $451,250 )
2024	2024	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	001	7	5/24/2024	NON-COMPETING CONTINUATION	$451,250
2024	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	5	5/21/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $451,250

Issue Date FY: 2023 ( Subtotal = $475,000 )
2023	2023	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	001	6	3/1/2023	COMPETING CONTINUATION	$475,000
2023	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	5	12/19/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $475,000

Issue Date FY: 2022 ( Subtotal = $425,933 )
2022	2022	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	5	6/8/2022	NON-COMPETING CONTINUATION	$425,933
														Subtotal = $425,933

Issue Date FY: 2021 ( Subtotal = $434,625 )
2021	2021	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	4	5/26/2021	NON-COMPETING CONTINUATION	$434,625
														Subtotal = $434,625

Issue Date FY: 2020 ( Subtotal = $434,625 )
2020	2020	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	3	5/20/2020	NON-COMPETING CONTINUATION	$434,625
														Subtotal = $434,625

Issue Date FY: 2019 ( Subtotal = $421,585 )
2019	2019	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	2	5/30/2019	NON-COMPETING CONTINUATION	$421,585
														Subtotal = $421,585

Issue Date FY: 2018 ( Subtotal = $434,625 )
2018	2018	VAN ANDEL RESEARCH INSTITUTE	333 BOSTWICK AVE NE	GRAND RAPIDS	MI	49503	KENT	USA	Cancer Biology Research	000	1	6/18/2018	NEW	$434,625
														Subtotal = $434,625

Grand Total All Awards = $3,552,643

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Molecular mechanisms of protein glycosylation and trafficking

Award Number: R01CA231466

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/18/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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