Tuesday, April 23, 2024 4/23/2024

Atomic-Resolution Analysis of eIF3-Mediated Translation Control

Award Number: R01GM065050
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY Protein biosynthesis directly couples genotype to phenotype in the cell, and its regulation is central to cellular physiology. Our understanding of the molecular mechanism of protein synthesis has undergone a revolution in the last decade, built on rapid advances in structural biology and systems biology. However, important questions relating to dynamic events in translation remain unanswered, as the transient nature of these events makes them difficult to isolate. In this application, we propose to decipher the molecular mechanisms of how eukaryotic translation initiation factor 3 (eIF3) in humans regulates translation initiation. We recently discovered that human eIF3 serves multiple roles in translation. Human eIF3 generally helps assemble translation preinitiation complexes at the start codon, but also directly controls the translation of specific mRNAs. We found that eIF3 can either activate or repress the translation of an mRNA, depending on how eIF3 binds to the mRNA's 5' untranslated region (5' UTR). Furthermore, we discovered that eIF3 harbors a subunit–EIF3D–that binds the 5'-m7G cap on certain mRNAs in an RNA structure-dependent manner. These discoveries indicate that eIF3 may integrate multiple signals to control the translational output of individual mRNAs, much like the Mediator complex in transcription. The aims in this application build on these groundbreaking results to address fundamental questions of how eIF3 functions. We propose to determine the structural basis for eIF3-mediated control of specialized translation, using cryo-electron microscopy (cryo-EM) and in vitro biochemistry. We will also probe how mRNAs regulated by eIF3 are structured in living cells, and dissect the functional importance of these structures to eIF3 regulation and the translational capacity of these mRNAs. Finally, we will use systems biological approaches to explore how eIF3 contributes to the regulation of translation mediated by N-6- methyladenosine (m6A) modifications in mRNAs. By combining advances in cryo-EM to our expertise in human cell engineering, we are in a unique position to unravel the molecular contributions of eIF3 to translation initiation in humans. Taken together, the three aims of this application build on the fundamental insights into eIF3 structure and function obtained in the prior funding period, and address key mechanisms in translational control that could be widespread in human biology. In the long run, our insights into the molecular mechanisms used in human cells to direct eIF3-mediated activation and repression of specific mRNAs could pave the way for the development of new small-molecule and cell-based therapeutics.


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 = -$920 )
2024	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	20	10/17/2023	NON-COMPETING CONTINUATION	-$920
														Subtotal = -$920

Issue Date FY: 2022 ( Subtotal = $361,683 )
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	20	12/22/2021	NON-COMPETING CONTINUATION	$325,514
2022	2022	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 201	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	001	20	7/27/2022	NON-COMPETING CONTINUATION	$36,169
														Subtotal = $361,683

Issue Date FY: 2021 ( Subtotal = $361,683 )
2021	2021	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	19	2/19/2021	NON-COMPETING CONTINUATION	$361,683
														Subtotal = $361,683

Issue Date FY: 2020 ( Subtotal = $361,683 )
2020	2020	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	000	18	1/13/2020	NON-COMPETING CONTINUATION	$361,683
														Subtotal = $361,683

Issue Date FY: 2019 ( Subtotal = $366,393 )
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	003	17	5/16/2019	COMPETING CONTINUATION	$1,270
2019	2019	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	001	17	1/11/2019	COMPETING CONTINUATION	$366,393
2019	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	16	1/8/2019	NON-COMPETING CONTINUATION	$0
2019	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	1608 4TH ST STE 220	BERKELEY	CA	94710	ALAMEDA	USA	Biomedical Research and Research Training	002	16	5/16/2019	NON-COMPETING CONTINUATION	-$1,270
														Subtotal = $366,393

Issue Date FY: 2017 ( Subtotal = $395,323 )
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	001	16	8/8/2017	NON-COMPETING CONTINUATION	$39,532
2017	2017	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	16	1/16/2017	NON-COMPETING CONTINUATION	$355,791
2017	2014	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	002	13	9/13/2017	COMPETING CONTINUATION	$77
2017	2013	REGENTS OF THE UNIVERSITY OF CALIFORNIA, THE	2150 SHATTUCK AVE RM 313	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	003	12	9/13/2017	SUPPLEMENT FOR EXPANSION	-$77
														Subtotal = $395,323

Issue Date FY: 2016 ( Subtotal = $443,854 )
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	001	15	3/1/2016	NON-COMPETING CONTINUATION	$39,532
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	002	15	9/19/2016	SUPPLEMENT FOR EXPANSION	$48,531
2016	2016	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	15	1/7/2016	NON-COMPETING CONTINUATION	$355,791
														Subtotal = $443,854

Issue Date FY: 2015 ( Subtotal = $386,977 )
2015	2015	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	14	1/21/2015	NON-COMPETING CONTINUATION	$386,977
														Subtotal = $386,977

Issue Date FY: 2014 ( Subtotal = $389,229 )
2014	2014	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	002	13	4/22/2014	COMPETING CONTINUATION	$389,229
2014	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	001	12	4/17/2014	SUPPLEMENT FOR EXPANSION	$0
2014	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	12	4/17/2014	NON-COMPETING CONTINUATION	$0
														Subtotal = $389,229

Issue Date FY: 2013 ( Subtotal = $126,264 )
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	002	12	4/17/2014	SUPPLEMENT FOR EXPANSION	$0
2013	2013	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	001	12	8/22/2013	SUPPLEMENT FOR EXPANSION	$126,264
2013	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	12	8/22/2013	NON-COMPETING CONTINUATION	$0
														Subtotal = $126,264

Issue Date FY: 2012 ( Subtotal = $371,807 )
2012	2012	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	12	7/13/2012	NON-COMPETING CONTINUATION	$371,807
														Subtotal = $371,807

Issue Date FY: 2011 ( Subtotal = $371,652 )
2011	2011	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	11	7/28/2011	NON-COMPETING CONTINUATION	$371,652
														Subtotal = $371,652

Issue Date FY: 2010 ( Subtotal = $378,904 )
2010	2010	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	10	7/19/2010	NON-COMPETING CONTINUATION	$378,904
														Subtotal = $378,904

Issue Date FY: 2009 ( Subtotal = $401,398 )
2009	2009	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	9	7/17/2009	COMPETING CONTINUATION	$401,398
														Subtotal = $401,398

Issue Date FY: 2008 ( Subtotal = $366,761 )
2008	2008	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	8	7/18/2008	NON-COMPETING CONTINUATION	$366,761
														Subtotal = $366,761

Issue Date FY: 2007 ( Subtotal = $366,852 )
2007	2007	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	7	7/13/2007	NON-COMPETING CONTINUATION	$366,852
														Subtotal = $366,852

Issue Date FY: 2006 ( Subtotal = $377,699 )
2006	2006	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	6	7/13/2006	NON-COMPETING CONTINUATION	$377,699
														Subtotal = $377,699

Issue Date FY: 2005 ( Subtotal = $364,993 )
2005	2005	UNIVERSITY OF CALIFORNIA, REGENTS	481 UNIVERSITY HALL	BERKELEY	CA	94704	ALAMEDA	USA	Biomedical Research and Research Training	000	5	7/18/2005	COMPETING CONTINUATION	$364,993
														Subtotal = $364,993

Issue Date FY: 2004 ( Subtotal = $302,145 ) (Continued on the next page)
Grand Total All Awards = $7,368,768

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Atomic-Resolution Analysis of eIF3-Mediated Translation Control

Award Number: R01GM065050

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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