9O5K

Cryo-EM structure of human SWELL1-PSA heterocomplex

Summary for 9O5K

• Entry DOI: 10.2210/pdb9o5k/pdb
• EMDB information: 70143
• Descriptor: Puromycin-sensitive aminopeptidase, Volume-regulated anion channel subunit LRRC8A (2 entities in total)
• Functional Keywords: hetero-complex, ion channel, modulator, membrane protein
• Biological source: Homo sapiens (human); More
• Total number of polymer chains: 9
• Total formula weight: 868449.21

Authors

Hagino, T.,Twomey, E.C.,Qiu, Z. (deposition date: 2025-04-10, release date: 2025-12-17, Last modification date: 2025-12-31)

Primary citation

Zheng, W.,Hagino, T.,Wang, H.,Cheng, H.Y.,Koylass, N.,Chen, K.H.,Wang, H.,Mani, S.,Mondal, A.K.,Twomey, E.C.,Qiu, Z.
Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.
Mol.Cell, 85:4621-4632.e7, 2025

PubMed 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 mechanism. Our findings identify PSA as an auxiliary subunit of VRACs, highlight the role of intracellular LRR domains in allosteric channel gating, and suggest a strategy to tune VRAC function in diverse physiological contexts, including 2'3'-cyclic GMP-AMP (cGAMP) transport and downstream stimulator of interferon genes (STING) signaling.

PubMed: 41371222
DOI: 10.1016/j.molcel.2025.11.014

Experimental method

ELECTRON MICROSCOPY (3.19 Å)