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A solid state conceptualization of information transfer from gene to message to protein

Award Number: R35GM130358
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: 02/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2029

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A solid state conceptualization of information transfer from gene to message to protein - Project Summary/Abstract: Normal proteins utilize most or all of life’s 20 amino acids to fold into stable structures responsible for their biological function. Perplexingly, between 10 and 20% of the proteins found in eukaryotic cells are unusual in containing only a subset of the 20 amino acid residues utilized by normal proteins. These unusual proteins are described as being of low sequence complexity and have long been understood to exist in states of intrinsic disorder. Despite constituting no more than 20% of the proteome, upwards of 75% of all forms of post-translational modification have been mapped to low complexity (LC) domains. It is likewise the case than more than 50% of all forms of alternative pre-mRNA splicing map to LC domains. These facts predict that a disproportionate amount of cellular regulation funnels through LC domains. More than a decade ago the group led by Dirk Gorlich at the Max Planck Institute for Biophysical Chemistry in Munich, Germany described the surprising ability of a low complexity domain to become phase separated in the form of a hydrogel. The work of Gorlich and colleagues was focused on the phenylalanine:glycine-rich low complexity (LC) domains of nucleoporin proteins, and their work offered a conceptual framework for understanding how the permeability barrier of the nuclear pore might work in a mechanistic sense. Parallel work by the McKnight lab in the Biochemistry Department of UT Southwestern Medical Center yielded similar findings in studies of the tyrosine:glycine-rich LC domain of the fused-in-sarcoma (FUS) RNA binding protein. In the latter case, self-association by the FUS LC domain was postulated to represent the basis by which RNA-rich membraneless granules form in the cytoplasm of eukaryotic cells. Over the past decade the McKnight laboratory investigated the concept that self-association of LC domains is mediated by the formation of labile cross-β structures poised at the threshold of thermodynamic equilibrium. In collaborative experiments with Robert Tycko at the National Institutes of Health, the McKnight group described the first atomic structure of a labile cross-β structure. This work revealed the chemical basis accounting for both the lability of the FUS structure and the specificity of self-association. It also showed that the structure was invariantly formed from the same, limited segment of the FUS LC domain. The structure-forming region of the FUS LC domain has come to be termed a labile, cross-β core. Similarly labile and invariantly localized cross-β cores have now been discovered within the LC domains of three other RNA binding proteins (hnRNPA2, TDP-43 and ataxin-2), the phenylalanine:glycine repeats of the Nup54 and Nup98 nucleoporin proteins, and the LC domains localized within the amino terminal segments of six different intermediate filament proteins. Extensive evidence has established that cross-β cores nucleate self-association, phase separation and the biological function of LC domains. This labile cross-β concept of LC domain self-association explains how phosphorylation of specific residues can disassemble both RNA granules and intermediate filaments, how methionine oxidation can disassemble labile cellular structures surrounding mitochondria, and how idiosyncratic human mutations within LC domains can aberrantly stabilize otherwise labile assemblies leading to neurological and neurodegenerative diseases.


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 = $479,700 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	002	7	1/27/2025	NON-COMPETING CONTINUATION	$479,700
2025	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	6	11/14/2024	COMPETING CONTINUATION	$0
2025	2023	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	5	12/30/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $479,700

Issue Date FY: 2024 ( Subtotal = $533,000 )
2024	2024	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	6	1/29/2024	COMPETING CONTINUATION	$533,000
														Subtotal = $533,000

Issue Date FY: 2023 ( Subtotal = $486,000 )
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	5	2/17/2023	NON-COMPETING CONTINUATION	$48,599
2023	2023	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	5	1/20/2023	NON-COMPETING CONTINUATION	$437,401
														Subtotal = $486,000

Issue Date FY: 2022 ( Subtotal = $486,000 )
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	4	2/2/2022	NON-COMPETING CONTINUATION	$437,401
2022	2022	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	4	6/30/2022	NON-COMPETING CONTINUATION	$48,599
														Subtotal = $486,000

Issue Date FY: 2021 ( Subtotal = $486,000 )
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	001	3	2/26/2021	NON-COMPETING CONTINUATION	$48,599
2021	2021	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	3	1/25/2021	NON-COMPETING CONTINUATION	$437,401
														Subtotal = $486,000

Issue Date FY: 2020 ( Subtotal = $486,000 )
2020	2020	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	2	1/9/2020	NON-COMPETING CONTINUATION	$486,000
														Subtotal = $486,000

Issue Date FY: 2019 ( Subtotal = $486,000 )
2019	2019	UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER, THE	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Biomedical Research and Research Training	000	1	1/4/2019	NEW	$486,000
														Subtotal = $486,000

Grand Total All Awards = $3,442,700

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A solid state conceptualization of information transfer from gene to message to protein

Award Number: R35GM130358

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: 02/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2029

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