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Dissecting the structure, function, and mechanisms of diverse protein-based metabolic organelles in bacteria

Award Number: R01AI081146
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract/Summary: Bacterial microcompartments (MCPs) are giant protein assemblies that serve as metabolic organelles in diverse bacteria found throughout the microbial world. These extraordinary structures are composed of thousands of subunits that assemble to form a polyhedral outer shell encapsulating a series of sequentially acting metabolic enzymes. MCPs typically encapsulate pathways that produce volatile or toxic intermediates that must be confined and metabolized to other compounds before diffusing out of the MCP and into the bacterial cytosol. MCPs confer special growth advantages to enteric bacteria and are linked to bacterial pathogenesis and the dissemination of enteric pathogens. Prior studies have focused primarily on selected MCP types, and important advances have been made. However, a number of mechanistic questions remain unanswered and some important MCP types are essentially uncharacterized. Prior work by our dual-PI team (Bobik and Yeates) focused primarily on the propanediol utilization (Pdu) MCP, which is used by Salmonella and other enteric bacteria to degrade 1,2-propanediol while sequestering a toxic intermediate, propionaldehyde. Our research in the previous cycle led to numerous important discoveries and critical insights into mechanistic aspects of how the Pdu MCP functions. Our key findings cover biological phenomena related to protein structure and assembly, molecular recognition, molecular transport, and molecular evolution. Our current proposal focuses on (1) remaining questions about the assembly and operation of the Pdu MCP of Salmonella, and (2) early-stage investigations into a new and diverse class of MCPs (which we identified bioinformatically) whose key internalized enzymes catalyze glycyl-radical-based reactions. Our continuing work on the Pdu MCP will answer outstanding questions about protein-protein interactions used to guide the assembly of the Pdu MCP– our earlier work led to the discovery of peptide targeting sequences that direct enzyme encapsulation by binding the interior surface of MCP shells. However, further experiments are required to paint a clearer picture about preferential associations by varied targeting sequences and their contribution to higher-order structural organization. In prior work, we also showed that pores through the shell proteins in the Pdu MCP have evolved for selective diffusive molecular transport of small molecules. In our continuing work, we propose experiments to investigate the dynamics and regulation of protein conformational changes that affect pore opening and closing in MCP shell proteins. The second part of the proposal focuses on the newly-defined and little-studied class of MCPs that encapsulate metabolic pathways dependent on glycyl-radical (Gr) enzymes. A number of Gr-MCPs are found in bacteria that inhabit the large intestine and which can infect the urinary tract. We will undertake work on three proposed Gr subtypes: one type that metabolizes 1,2- PD (similarly to the Pdu system but using unrelated enzymes), and two distinct subtypes that are believed to metabolize choline. Our new research on the Gr systems will lay the foundations for understanding their unique structures and mechanisms. We will answer questions about their composition, metabolic function, organization, and structure. As with our studies of the Pdu MCP, our interdisciplinary work will be guided by structural and genetic studies, especially of diverse shell proteins and the properties of their pores, which are at the heart of molecular transport phenomena in these systems. The Pdu and Gr systems will also be compared and contrasted to gain insights into the principles that underlie functional diversification of bacterial MCPs.


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 = $0 )
2024	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	12	2/25/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $588,223 )
2022	2022	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	12	5/3/2022	NON-COMPETING CONTINUATION	$588,223
														Subtotal = $588,223

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	11	5/28/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $588,223 )
2020	2020	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	11	4/8/2020	NON-COMPETING CONTINUATION	$588,223
														Subtotal = $588,223

Issue Date FY: 2019 ( Subtotal = $588,223 )
2019	2019	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	515 MORRILL RD, 1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	10	4/16/2019	NON-COMPETING CONTINUATION	$588,223
														Subtotal = $588,223

Issue Date FY: 2018 ( Subtotal = $588,223 )
2018	2018	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	9	4/18/2018	NON-COMPETING CONTINUATION	$588,223
														Subtotal = $588,223

Issue Date FY: 2017 ( Subtotal = $600,723 )
2017	2017	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	002	8	8/21/2017	COMPETING CONTINUATION	$54,908
2017	2017	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	8	1/30/2017	COMPETING CONTINUATION	$600,723
2017	2016	IOWA STATE UNIVERSITY OF SCIENCE AND TECHNOLOGY	1350 BEARDSHEAR HALL	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	7	8/21/2017	EXTENSION WITH OR WITHOUT FUNDS	-$54,908
														Subtotal = $600,723

Issue Date FY: 2016 ( Subtotal = $484,465 )
2016	2016	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	7	4/13/2016	EXTENSION WITH OR WITHOUT FUNDS	$484,465
														Subtotal = $484,465

Issue Date FY: 2015 ( Subtotal = $484,465 )
2015	2015	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	6	4/16/2015	NON-COMPETING CONTINUATION	$484,465
														Subtotal = $484,465

Issue Date FY: 2014 ( Subtotal = $484,465 )
2014	2014	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	5	4/16/2014	NON-COMPETING CONTINUATION	$484,465
														Subtotal = $484,465

Issue Date FY: 2013 ( Subtotal = $455,397 )
2013	2013	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	4	6/3/2013	NON-COMPETING CONTINUATION	$19,379
2013	2013	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	000	4	4/5/2013	NON-COMPETING CONTINUATION	$436,018
														Subtotal = $455,397

Issue Date FY: 2012 ( Subtotal = $496,465 )
2012	2012	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Allergy and Infectious Diseases Research	001	3	4/16/2012	COMPETING CONTINUATION	$496,465
2012	2010	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Trans-NIH Recovery Act Research Support	000	2	4/16/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $496,465

Issue Date FY: 2010 ( Subtotal = $545,728 )
2010	2010	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Trans-NIH Recovery Act Research Support	000	2	6/24/2010	NON-COMPETING CONTINUATION	$545,728
														Subtotal = $545,728

Issue Date FY: 2009 ( Subtotal = $563,501 )
2009	2009	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Trans-NIH Recovery Act Research Support	001	1	7/30/2009	NEW	-$4,119
2009	2009	IOWA STATE UNIVERSITY OF SCIENCE & TECHNOLOGY	3609 ADMINISTRATIVE SVCS BLDG	AMES	IA	50011	STORY	USA	Trans-NIH Recovery Act Research Support	000	1	7/15/2009	NEW	$567,620
														Subtotal = $563,501

Grand Total All Awards = $6,468,101

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Dissecting the structure, function, and mechanisms of diverse protein-based metabolic organelles in bacteria

Award Number: R01AI081146

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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