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Integrated studies of DEAD-box ATPase function during large ribosomal subunit maturation

Award Number: R01GM135617
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Integrated studies of DEAD-box ATPase function during large ribosomal subunit maturation - The assembly of ribonucleoprotein (RNP) complexes is central to processes such as protein translation, mRNA splicing, and telomere maintenance. ATPases of the DEAD-box family are ubiquitous, highly conserved enzymes that play essential roles during RNP assembly in all kingdoms of life. DEAD-box proteins play critical roles in human health and disease; defects in DEAD-box proteins underlie the progression of specific cancers as well as developmental disorders, and are co-opted by RNA viruses such as HIV and West Nile for viral RNA processing. Though they are part of the SF2 family of helicases, DEAD-box proteins lack key domains present in processive SF2 helicases, and rely instead on trans factors that regulate ATP hydrolysis and substrate binding. During RNP assembly, ATPase activity has been proposed to drive the remodeling of secondary and tertiary RNA structures, coordinating the ordered addition of proteins to form functional RNP assemblies. The requirement of trans modulators makes DEAD-box ATPases ideal regulators, integrating RNP biogenesis with cellular signaling. However, due to the transient nature of their interactions, we have no molecular understanding of the how DEAD-box proteins engage and remodel their RNP assembly substrates. This proposal describes a hybrid approach to define the molecular details of four essential DEAD-box proteins (Dbp10, Drs1, Spb4 and Mak5) during the assembly of a complex RNP, the large ribosomal (60S) subunit. We genetically manipulated yeast strains to trap and enrich distinct, transient DEAD-box·RNP intermediates. The structural characterization of these dynamic complexes by cryo-electron microscopy, as part of an integrated approach that includes cross- linking mass-spectrometry and targeted in vitro reconstitution experiments, will shed light on the molecular interactions of DEAD-box proteins with substrate RNA and modulating co- factors. Because DEAD-box modulation of 60S maturation is closely associated with the regulation of nucleolar pre-60S release, we will use a color-switching yeast strain to probe the effect the expression of Dbp10, Drs1, Mak5 and Spb4 trapping mutants have on the subcellular distribution of 60s intermediates. Together, these studies represent a unique approach to understand the function of DEAD-box proteins in the centrally important 60S biogenesis pathway. These innovative reagents and their use within an integrative experimental approach will uniquely inform how DEAD-box proteins engage transient, dynamic intermediates to modulate RNP assembly.


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: 2024 ( Subtotal = $340,172 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	5	6/25/2024	NON-COMPETING CONTINUATION	$34,017
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	12/15/2023	NON-COMPETING CONTINUATION	$306,155
														Subtotal = $340,172

Issue Date FY: 2023 ( Subtotal = $340,172 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	4	3/8/2023	NON-COMPETING CONTINUATION	$34,017
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	4	12/2/2022	NON-COMPETING CONTINUATION	$306,155
														Subtotal = $340,172

Issue Date FY: 2022 ( Subtotal = $340,172 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	3	7/28/2022	NON-COMPETING CONTINUATION	$34,018
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	3	12/21/2021	NON-COMPETING CONTINUATION	$306,154
														Subtotal = $340,172

Issue Date FY: 2021 ( Subtotal = $339,494 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	2	3/16/2021	NON-COMPETING CONTINUATION	$33,951
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	12/15/2020	NON-COMPETING CONTINUATION	$305,543
														Subtotal = $339,494

Issue Date FY: 2020 ( Subtotal = $338,477 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	12/23/2019	NEW	$338,477
														Subtotal = $338,477

Grand Total All Awards = $1,698,487

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Integrated studies of DEAD-box ATPase function during large ribosomal subunit maturation

Award Number: R01GM135617

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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