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Principles of selectivity and translocation in transition metal transporters, metallochaperones, and associated metalloproteins

Award Number: R35GM128704
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Abstract In all living organisms, transition metals are essential trace elements. Their unique chemical properties are exploited in metalloenzymes, metalloproteins, and as signaling ions, to perform key biochemical processes. Integrated metal uptake, distribution, storage, and sensing protein networks guarantee that essential metals are delivered to their correct targets, while toxic metals are selectively removed from the cellular environment. Transmembrane metal transporters and interacting metallochaperones are key hubs that selectively regulate the fluxes of metals across cellular membranes. The chemical, molecular and structural principles that govern metal transporter cargo selectivity, promiscuity, translocation, and substrate delivery by metallochaperones and associated metalloproteins are elusive. We developed a strategy that leverages integrated chemical, biophysical, and structural approaches to determine how metal selection and transport occurs in transporter families featuring different topologies, transport mechanisms, and energetics. This MIRA application targets the study of primary active metal pumps, secondary active solute carriers (SLC), and ion facilitators to address: i) the bioinorganic and coordination chemistry determinants controlling substrate selectivity, affinity, and kinetic lability for rapid translocation across membranes; ii) how conserved structural frameworks in transporter families are adapted to diversify cargo specificity towards essential 1st-row and toxic 2nd/3rd-row transition metals; iii) how energy transduction and conformational changes are coupled to substrate transport; and iv) the chemical, thermodynamic, kinetic, and structural principles that control metal delivery and uptake to/from transporters by metallochaperones. The program will target metal transporters involved in metal homeostasis, disease progression, and pathogen virulence: 1) copper and zinc P-type ATPase pumps and their metallochaperones, which control copper levels in humans and Cu/Zn concentrations in bacteria acting as virulence factors; 2) TMEM205, that we discovered as a new human copper/platinum transporter involved in Cu(I)-homeostasis and anti-cancer Pt-drug resistance, and TMEM52B as its putative chaperone; 3) Fe(II)-selective prokaryotic and eukaryotic transporters belonging to the IroT, ZIP and CDF families, responsible for iron acquisition and virulence in pathogens causing bacterial infections and neglected tropical diseases; and 4) prokaryotic nickel and cobalt transporters controlling essential acquisition of scarce trace elements for Ni/Co enzyme maturation. We will combine biophysical, spectroscopic, and structural transporter characterization in detergents with the study of substrate translocation events in real-time in native-like lipid bilayer systems, using the innovative fluorescence multi-probe platform that we established in our group. We expect to reveal new paradigms underlying transport kinetics, thermodynamics and mechanism in metal transporters. By targeting neglected aspects of bioinorganic chemistry in biomedically relevant systems with potential for translational applications, we expect to contribute to fundamental understanding of metal transport processes across biological membranes in health and disease.


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: 2025 ( Subtotal = $383,292 )
2025	2025	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	003	7	11/19/2024	NON-COMPETING CONTINUATION	$383,292
2025	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	002	6	11/7/2024	COMPETING CONTINUATION	$1,375
2025	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	6	11/5/2024	COMPETING CONTINUATION	$0
2025	2022	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	5	11/7/2024	NON-COMPETING CONTINUATION	-$1,375
														Subtotal = $383,292

Issue Date FY: 2024 ( Subtotal = $530,880 )
2024	2024	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	6	1/8/2024	COMPETING CONTINUATION	$530,880
2024	2022	UNIVERSITY OF TEXAS AT DALLAS	800 WEST CAMPBELL RD.	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	5	12/29/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $530,880

Issue Date FY: 2022 ( Subtotal = $380,661 )
2022	2022	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	5	6/7/2022	NON-COMPETING CONTINUATION	$380,661
														Subtotal = $380,661

Issue Date FY: 2021 ( Subtotal = $627,061 )
2021	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	4	6/10/2021	NON-COMPETING CONTINUATION	$380,661
2021	2021	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	001	4	7/12/2021	SUPPLEMENT FOR EXPANSION	$246,400
														Subtotal = $627,061

Issue Date FY: 2020 ( Subtotal = $377,601 )
2020	2020	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	3	6/16/2020	NON-COMPETING CONTINUATION	$377,601
														Subtotal = $377,601

Issue Date FY: 2019 ( Subtotal = $376,836 )
2019	2019	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	2	6/21/2019	NON-COMPETING CONTINUATION	$376,836
														Subtotal = $376,836

Issue Date FY: 2018 ( Subtotal = $377,197 )
2018	2018	UNIVERSITY OF TEXAS AT DALLAS	800 W CAMPBELL RD	RICHARDSON	TX	75080	DALLAS	USA	Biomedical Research and Research Training	000	1	6/29/2018	NEW	$377,197
														Subtotal = $377,197

Grand Total All Awards = $3,053,528

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Principles of selectivity and translocation in transition metal transporters, metallochaperones, and associated metalloproteins

Award Number: R35GM128704

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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