Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.

ABSTRACT: Volume-regulated anion channels (VRACs) are large-pore channels expressed in most vertebrate cells and are critical for cell volume regulation and autocrine/paracrine signaling. Here, we identify the ubiquitously expressed puromycin-sensitive aminopeptidase (PSA) as a binding partner of the obligatory VRAC subunit SWELL1 (also known as LRRC8A) and determine the cryo-electron microscopy structure of the SWELL1-PSA complex. Three PSA molecules bind a single SWELL1 hexamer, coupling adjacent leucine-rich repeat (LRR) domains into local dimers. Functionally, PSA overexpression suppresses VRAC activation, whereas PSA deletion dramatically elevates basal channel activity. Notably, PSA's modulation of VRACs requires physical binding but not aminopeptidase activity, indicating a structural mechani

SUBMITTER: Zheng W 

PROVIDER: S-EPMC12698191 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature