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Structure and Function of Porphyromonas gingivalis Type IX Secretion System

Award Number: R01DE033452
ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2024
PERIOD OF PERFORMANCE END DATE: 12/31/2028

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Structure and Function of Porphyromonas gingivalis Type IX Secretion System - Many bacterial pathogens deploy specialized secretion systems to deliver virulence factors to eukaryotic host cells or the environment. Type IX secretion system (T9SS) of Porphyromonas gingivalis, a periodontal pathogen, mediates secretion of extracellular and cell-surface-bound substrates including gingipain proteases. Our knowledge of T9SS structures has largely derived from X-ray crystallography and single-particle electron microscopy approaches, which by definition is limited to solving structures of subcomplexes amenable to isolation and purification. However, revolutionary advances in in situ cryo-electron tomography (Cryo-ET) are now enabling visualization of T9SS in the native context of the bacterial cell envelope. Drs. Hu and Lamont have been at the forefront of this work, and we have now visualized the intact T9SS of P. gingivalis in situ. The T9SS is unique, presenting not as a single functional entity, as do all other known bacterial and eukaryotic protein transport systems, but rather as a composite of seemingly independent translocation motors and Sov translocons, arranged symmetrically as distinct rings in the cytoplasm, periplasm, and cell surface. The long-term objective of our work is to comprehensively define structure & function of the T9SS in the periodontal pathogen P. gingivalis. In this application, we will continue to exploit in situ Cryo-ET approaches to solve structures of T9SS machines from wild-type and mutant strains, and we will integrate complementary biochemical and other electron and fluorescence microscopy approaches to add depth to the Cryo-ET studies and to evaluate the spatial organization of subunits and function of T9SS. In Aim 1, we will refine the in situ structures at high resolution (10-15 Å) and integrate analyses of mutant machines to map individual machine subunits. We will seek to determine the PorK/N complex structure at near-atomic resolution by Cryo-EM. We will also determine the stoichiometry of the Sov translocon by fluorescence microscopy. Aim 2 will complete ongoing work aimed at identifying structural changes accompanying activation of the T9SS upon sensing of PMF. We will inhibit energy transduction via mutagenesis of key residues of the molecular motor PorM/L to detect any structural changes within the T9SS, and define the interaction domains between PorM and PorKN, which will shed light on the mechanism of energy transduction from PorM to the PorKN complex. We anticipate that our studies will provide a structural basis for T9SS mediated translocation of virulence factors and a foundation for development of intervention strategies to suppress P. gingivalis virulence.


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: 2026 ( Subtotal = $342,947 )
2026	2026	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	3	12/4/2025	NON-COMPETING CONTINUATION	$342,947
														Subtotal = $342,947

Issue Date FY: 2025 ( Subtotal = $381,052 )
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	2	1/6/2025	NON-COMPETING CONTINUATION	$342,947
2025	2025	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	2	5/6/2025	NON-COMPETING CONTINUATION	$38,105
														Subtotal = $381,052

Issue Date FY: 2024 ( Subtotal = $395,052 )
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	001	1	12/21/2023	NEW	-$395,052
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	000	1	12/21/2023	NEW	$395,052
2024	2024	UNIVERSITY OF TEXAS HEALTH SCIENCE CENTER AT HOUSTON	7000 FANNIN ST FL 9	HOUSTON	TX	77030	HARRIS	USA	Oral Diseases and Disorders Research	002	1	1/19/2024	NEW	$395,052
														Subtotal = $395,052

Grand Total All Awards = $1,119,051

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Structure and Function of Porphyromonas gingivalis Type IX Secretion System

Award Number: R01DE033452

ORGANIZATION: NATIONAL INSTITUTE OF DENTAL AND CRANIOFACIAL RESEARCH

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2024

PERIOD OF PERFORMANCE END DATE: 12/31/2028

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