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The Conformational Dynamics of eIF5B During Ribosomal Subunit Joining

Award Number: F32GM139360
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 11/18/2022

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The Conformational Dynamics of eIF5B During Ribosomal Subunit Joining - ABSTRACT Translation initiation in eukaryotes, which requires over a dozen eukaryotic initiation factors (eIFs), is a highly regulated process that helps establish the fidelity of protein synthesis and is directly targeted during cellular stress and disease. To add to the complexity of this process, ribosomal initiation complexes (ICs) undergo multiple conformational rearrangements upon eIF binding and activity, and dysregulation of the associated conformational changes are thought to underlie cellular stress and disease. Despite the importance of these molecular rearrangements for the function of the translation machinery, current structural approaches cannot resolve the real-time dynamics of the eIF binding events and IC structural rearrangements that are inferred from comparisons of the static structural snapshots provided by X-ray crystallographic and cryogenic electron microscopy studies. This presents a gap in our understanding of how eIF binding and eIF- and ribosome structural rearrangements cooperatively ensure the fidelity of translation initiation. Specifically, the last step in the initiation pathway, in which the large ribosomal subunit joins to the IC, functions as a final regulatory checkpoint in the pathway. This step is regulated by the translational guanosine triphosphatase (GTPase) eIF 5B and eIF 1A. Specifically, 5B accelerates the subunit joining step in a GTP- and methionylated initiator tRNA (Met-tRNAi)-dependent manner that is facilitated by 1A. This leads to questions such as: Do dynamic structural rearrangements of 5B underlie its ability to accelerate subunit joining? If so, how do GTP and Met-tRNAi modulate the dynamics of 5B? Likewise, how does 1A modulate the dynamics of 5B and how does such modulation regulate the ability of 5B to recognize Met-tRNAi, accelerate subunit joining, and undergo GTP hydrolysis upon subunit joining? To address these questions, I will use a combination of advanced single- molecule Förster Resonance Energy Transfer (smFRET) techniques and ensemble biochemical and biophysical approaches to characterize the dynamic structural rearrangements of 5B, 1A, and the IC during subunit joining, and elucidate the contributions that these dynamics make to the mechanism and regulation of translation initiation. The immediate goal of this proposal is to dissect the conformational dynamics and kinetics of 5B and 1A, demonstrating how these eIFs couple Met-tRNAi recognition to acceleration of subunit joining, GTP hydrolysis by 5B, and dissociation of 5B and 1A following productive subunit joining.


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: 2023 ( Subtotal = -$6,749 )
2023	2022	THE TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK	615 W 131ST ST	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	001	2	9/27/2023	NON-COMPETING CONTINUATION	$0
2023	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	2	3/29/2023	NON-COMPETING CONTINUATION	-$6,749
														Subtotal = -$6,749

Issue Date FY: 2022 ( Subtotal = $69,802 )
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	002	2	9/14/2022	NON-COMPETING CONTINUATION	$0
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	001	2	6/6/2022	NON-COMPETING CONTINUATION	$1,240
2022	2022	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	202 LOW LIBRARY 535 W 116 ST MC 4309,	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	2	12/31/2021	NON-COMPETING CONTINUATION	$68,562
														Subtotal = $69,802

Issue Date FY: 2020 ( Subtotal = $65,310 )
2020	2020	TRUSTEES OF COLUMBIA UNIVERSITY IN THE CITY OF NEW YORK, THE	116TH AND BDWY	NEW YORK	NY	10027	NEW YORK	USA	Biomedical Research and Research Training	000	1	7/1/2020	NEW	$65,310
														Subtotal = $65,310

Grand Total All Awards = $128,363

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The Conformational Dynamics of eIF5B During Ribosomal Subunit Joining

Award Number: F32GM139360

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 11/18/2022

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