Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3

Gupta, Ankit ; Mahalakshmi, Radhakrishnan (2019) Helix–strand interaction regulates stability and aggregation of the human mitochondrial membrane protein channel VDAC3 The Journal of General Physiology, 151 (4). pp. 489-504. ISSN 0022-1295

Full text not available from this repository.

Official URL: http://doi.org/10.1085/jgp.201812272

Related URL: http://dx.doi.org/10.1085/jgp.201812272

Abstract

Voltage-dependent anion channels (VDACs) are β-sheet–rich transmembrane β-barrels that are vital for metabolite transport across the mitochondrial membrane. Under cellular stress, human VDACs hetero-oligomerize and coaggregate with proteins that can form amyloidogenic and neurodegenerative deposits, implicating a role for VDACs in proteotoxicity. However, whether VDACs possess intrinsic interaction sites that can lead to protein aggregation is not known. Here, we couple a systematic thiol replacement strategy with far-UV circular dichroism spectropolarimetry and UV scattering spectroscopy to map aggregation-prone regions of human VDACs, using isoform 3 as our model VDAC. We show that the region comprising strands β7–β9 is highly aggregation prone. Further, we find that an α1–β7–β9 interaction (involving the hVDAC3 N-terminal α1 helix) can lower protein aggregation, whereas perturbations of this interaction promote VDAC aggregation. We also show that hVDAC3 aggregation proceeds via a partially unfolded structure. Our findings allow us to propose a plausible mechanism for the role of human VDACs in forming proteotoxic aggregates in the cell. The key target sites on VDACs—strands β7–β9—may be useful for developing VDAC aggregation inhibitors.

Item Type:Article
Source:Copyright of this article belongs to Rockefeller University Press.
ID Code:136802
Deposited On:20 Aug 2025 11:18
Last Modified:20 Aug 2025 11:18

Repository Staff Only: item control page