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Structural and mechanistic basis of AAGAB-controlled AP2 adaptor assembly

Award Number: R01GM138685
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: 07/13/2020
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Structural and mechanistic basis of AAGAB-controlled AP2 adaptor assembly - PROJECT SUMMARY In clathrin-mediated endocytosis (CME), the coat protein clathrin relies on adaptors to recruit cargo proteins to endocytic sites. The predominant clathrin adaptor in CME is the heterotetrameric AP2 adaptor complex, which is comprised of two large subunits ( and β), one medium subunit (µ), and one small subunit (). It is generally thought that multimeric trafficking adaptors such as AP2 adaptor assemble spontaneously. However, we recently discovered that AP2 adaptor assembly is an ordered process controlled by alpha and gamma adaptin binding protein (AAGAB). Without the assistance of AAGAB, AP2 adaptor fails to form, leading to CME defects. These findings revealed a previously unrecognized pathway in clathrin-mediated trafficking. However, it remains unclear how AAGAB recognizes AP2 subunits and how AAGAB-AP2 interactions drive AP2 adaptor assembly. In our preliminary studies, we expressed and purified free AAGAB and AAGAB:AP2 assembly intermediates, and gained initial insights into their structures and functions. In this research, we will take advantage of these preliminary data to determine the structural and mechanistic basis of AAGAB-controlled AP2 adaptor assembly. We will first characterize the biochemical properties of free AAGAB and AAGAB:AP2 assembly intermediates using reconstituted systems. We will then determine the atomic structures of the proteins and protein complexes using X-ray crystallography and single-particle cryo-electron microscopy. Next, we will validate the physiological relevance of the biochemical and structural findings using cell-based genetic assays. Finally, we will determine how AAGAB functions are impacted by disease-causing mutations. Successful completion of this proposed research will fill a major gap in our knowledge of membrane protein trafficking. This work will also serve as a paradigm for understanding the assembly of trafficking adaptors in general. Ultimately, these findings will facilitate the development of novel therapeutic strategies for human diseases caused by AAGAB mutations.


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 = $0 )
2025	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	5/30/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $342,615 )
2023	2023	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	4	5/23/2023	NON-COMPETING CONTINUATION	$342,615
														Subtotal = $342,615

Issue Date FY: 2022 ( Subtotal = $343,428 )
2022	2022	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	3	5/16/2022	NON-COMPETING CONTINUATION	$343,428
														Subtotal = $343,428

Issue Date FY: 2021 ( Subtotal = $344,202 )
2021	2021	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	2	5/21/2021	NON-COMPETING CONTINUATION	$344,202
														Subtotal = $344,202

Issue Date FY: 2020 ( Subtotal = $358,892 )
2020	2020	FLORIDA STATE UNIVERSITY	874 TRADITIONS WAY	TALLAHASSEE	FL	32306	LEON	USA	Biomedical Research and Research Training	000	1	7/13/2020	NEW	$358,892
														Subtotal = $358,892

Grand Total All Awards = $1,389,137

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Structural and mechanistic basis of AAGAB-controlled AP2 adaptor assembly

Award Number: R01GM138685

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: 07/13/2020

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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