Thursday, November 21, 2024 11/21/2024

Structural basis of the gating mechanism of connexin 26 and related hearing loss

Award Number: R21DC019476
ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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SUMMARY Connexin 26, as a gap junction channel, directly regulates the cell-to-cell exchange of ion, metabolites, and second messengers. Mutations of connexin 26 can cause severe hearing loss. However, the molecular gating mechanism on the structural basis of connexin 26 is still unclear, especially the closed state and malfunction of connexin 26 mutations. We have developed the native cell membrane nanoparticle (NCMN) system for high-resolution single-particle cryo-EM structure determination and functional studies of membrane proteins within their physiological conditions. We recently solved the cryo-EM structures of connexin 26 in the absence or presence of calcium ions in an open state at 2.3 Å and 2.9 Å associated with about 36 lipid molecules via the NCMN system. However, the close state of connexin 26 with high resolution is still uncovered. We hypothesize that our NCMN system's application to structure determination of Cx26 and Cx26-R75W in the presence and absence of calcium and calmodulin can provide unique structural information. Aim 1: To investigate the CLOSED conformation of the gating mechanism of Cx26. Aim 2: To elucidate the molecular basis of how the single point mutation R75W in Cx26 leads to profound hearing loss. The proposed experimental results will provide insights into detailed structural information and biochemical analysis in understanding the gating mechanism, also provide mechanistic details on abnormal channel gating function detected in this hearing disorder. The structural information may lead to some novel strategy to modulate the malfunction CX26-R75W for hearing loss.


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	2022	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Research Related to Deafness and Communication Disorders	000	2	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $194,063 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Research Related to Deafness and Communication Disorders	000	2	6/22/2022	NON-COMPETING CONTINUATION	$194,063
														Subtotal = $194,063

Issue Date FY: 2021 ( Subtotal = $229,008 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Research Related to Deafness and Communication Disorders	000	1	7/9/2021	NEW	$229,008
														Subtotal = $229,008

Grand Total All Awards = $423,071

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Structural basis of the gating mechanism of connexin 26 and related hearing loss

Award Number: R21DC019476

ORGANIZATION: NATIONAL INSTITUTE ON DEAFNESS AND OTHER COMMUNICATION DISORDERS

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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