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Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity

Award Number: SC3GM116745
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: 04/01/2016
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity - PROJECT SUMMARY / ABSTRACT Background. Pathogenic bacteria must travel through the highly acidic environment of the stomach before they can reach and infect the intestines. The stomach is therefore an important barricade which helps to kill many bacteria before they can cause illness. In some of the most infectious bacteria, however, ATP- independent chaperones HdeA and HdeB play major roles in aiding bacterial survival at low pH. Their job is to protect other proteins from misfolding and aggregating as the cell transitions through the harsh environment of the stomach and into the neutral environment of the intestines. HdeB is active at intermediate pH values, while HdeA functions at the low pH typical of stomach acid. Although there are various models available to explain the interplay between the two chaperones, it is still unclear which, if any, is correct. Specific aims. The goal of the proposed work is to use NMR spectroscopy and other biophysical techniques to pursue an in-depth investigation of the apparently synergistic mechanism by which the two chaperone proteins operate and to probe the roles of specific residues that trigger or modify the activation of HdeA or HdeB. Aim #1 is to examine the roles and interactions of HdeA and HdeB with chaperone clients as a function of pH. Isotopic labeling and the unique properties of NMR spectroscopy will be employed to monitor each protein individually within a mixture of HdeA, HdeB and a client protein, thereby providing different vantage points to obtain unprecedented detail. Aim #2 is to probe sites of chaperone activation and stability in HdeA and HdeB using targeted mutations. Here, a variety of techniques will be used to closely assess segments of each protein that have been linked to essential roles in function and/or activation, including a key tryptophan in the dimer interface of HdeB and the disulfide bond in HdeA, which helps to maintain the semi-folded structure believed to be important to its chaperone function. Health-related significance. Dysentery, caused by intestinal infection by pathogenic bacteria, kills at least 350,000 people per year worldwide. If we can elucidate the individual and collective roles of HdeA and HdeB in the presence of client proteins, as well as the mechanistic importance of specific residues or regions, we can better understand how these acid-stress chaperones help bacteria survive under extreme conditions. Improved understanding can inform researchers designing vaccines or other therapeutics that can disable the activities of HdeA and HdeB and thereby weaken the infectivity of these pathogenic bacteria.


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 = $108,750 )
2024	2024	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	8	7/4/2024	NON-COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2023 ( Subtotal = $107,156 )
2023	2023	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	7	7/31/2023	NON-COMPETING CONTINUATION	$108,750
2023	2019	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	2/2/2023	NON-COMPETING CONTINUATION	-$1,594
														Subtotal = $107,156

Issue Date FY: 2022 ( Subtotal = $108,750 )
2022	2022	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	6	8/10/2022	NON-COMPETING CONTINUATION	$108,750
2022	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	5	5/17/2022	COMPETING CONTINUATION	$19,651
2022	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	5/17/2022	NON-COMPETING CONTINUATION	-$19,651
														Subtotal = $108,750

Issue Date FY: 2021 ( Subtotal = $108,750 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	002	5	9/10/2021	COMPETING CONTINUATION	$108,750
2021	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	4/1/2021	NON-COMPETING CONTINUATION	$0
2021	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	4	9/8/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $108,750

Issue Date FY: 2019 ( Subtotal = $108,750 )
2019	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	4/2/2019	NON-COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2018 ( Subtotal = $108,750 )
2018	2018	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	2/27/2018	NON-COMPETING CONTINUATION	$97,875
2018	2018	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	3	5/11/2018	NON-COMPETING CONTINUATION	$10,875
														Subtotal = $108,750

Issue Date FY: 2017 ( Subtotal = $108,750 )
2017	2017	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	3/16/2017	NON-COMPETING CONTINUATION	$97,875
2017	2017	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	001	2	6/20/2017	NON-COMPETING CONTINUATION	$10,875
														Subtotal = $108,750

Issue Date FY: 2016 ( Subtotal = $108,750 )
2016	2016	THE UNIVERSITY CORPORATION	18111 NORDHOFF STREET	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	3/25/2016	NEW	$108,750
														Subtotal = $108,750

Grand Total All Awards = $868,406

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Synergy between acid stress chaperones HdeA and HdeB with clients and their key sites of activity

Award Number: SC3GM116745

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: 04/01/2016

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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