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- EMDB-70143: Cryo-EM structure of human SWELL1-PSA heterocomplex -

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Basic information

Entry
Database: EMDB / ID: EMD-70143
TitleCryo-EM structure of human SWELL1-PSA heterocomplex
Map data
Sample
  • Complex: Heterocomplex of SWELL1 and PSA
    • Protein or peptide: Puromycin-sensitive aminopeptidase
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A
KeywordsHetero-complex / Ion channel / Modulator / MEMBRANE PROTEIN
Function / homology
Function and homology information


cytosol alanyl aminopeptidase / pre-B cell differentiation / Miscellaneous transport and binding events / aspartate transmembrane transport / alanyl aminopeptidase activity / volume-sensitive anion channel activity / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / taurine transmembrane transport / monoatomic anion transmembrane transport ...cytosol alanyl aminopeptidase / pre-B cell differentiation / Miscellaneous transport and binding events / aspartate transmembrane transport / alanyl aminopeptidase activity / volume-sensitive anion channel activity / cyclic-GMP-AMP transmembrane transporter activity / cyclic-GMP-AMP transmembrane import across plasma membrane / taurine transmembrane transport / monoatomic anion transmembrane transport / protein hexamerization / cell volume homeostasis / monoatomic anion transport / response to osmotic stress / : / peptide catabolic process / intracellular glucose homeostasis / metalloaminopeptidase activity / monoatomic ion channel complex / positive regulation of myoblast differentiation / aminopeptidase activity / peptide binding / chloride transmembrane transport / positive regulation of insulin secretion / protein polyubiquitination / Antigen processing: Ubiquitination & Proteasome degradation / spermatogenesis / cellular response to hypoxia / intracellular signal transduction / lysosomal membrane / cell surface / proteolysis / extracellular space / extracellular exosome / zinc ion binding / identical protein binding / nucleus / membrane / plasma membrane / cytosol / cytoplasm
Similarity search - Function
LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / Aminopeptidase N-type / ERAP1-like C-terminal domain / : / ERAP1-like C-terminal domain / : / : / Leucine-rich repeat region / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase ...LRRC8, pannexin-like TM region / Pannexin-like TM region of LRRC8 / Aminopeptidase N-type / ERAP1-like C-terminal domain / : / ERAP1-like C-terminal domain / : / : / Leucine-rich repeat region / Peptidase M1, alanine aminopeptidase/leukotriene A4 hydrolase / Peptidase M1, membrane alanine aminopeptidase / Aminopeptidase N-like , N-terminal domain / Peptidase family M1 domain / Peptidase M1 N-terminal domain / Aminopeptidase N-like , N-terminal domain superfamliy / Leucine-rich repeat, SDS22-like subfamily / Peptidase M4/M1, CTD superfamily / Leucine rich repeat / Leucine-rich repeat, typical subtype / Leucine-rich repeats, typical (most populated) subfamily / Leucine-rich repeat profile. / Leucine-rich repeat / Leucine-rich repeat domain superfamily / Neutral zinc metallopeptidases, zinc-binding region signature.
Similarity search - Domain/homology
Puromycin-sensitive aminopeptidase / Volume-regulated anion channel subunit LRRC8A
Similarity search - Component
Biological speciesHomo sapiens (human)
Methodsingle particle reconstruction / cryo EM / Resolution: 3.19 Å
AuthorsHagino T / Twomey EC / Qiu Z
Funding support United States, 1 items
OrganizationGrant numberCountry
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM124824 United States
CitationJournal: Mol Cell / Year: 2025
Title: Puromycin-sensitive aminopeptidase acts as an inhibitory auxiliary subunit of volume-regulated anion channels and regulates cGAMP transport.
Authors: Wenqiang Zheng / Tatsuya Hagino / Hao Wang / Henry Yi Cheng / Nicholas Koylass / Kevin Hong Chen / Haobo Wang / Sepehr Mani / Anish Kumar Mondal / Edward C Twomey / Zhaozhu Qiu /
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 ...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.
History
DepositionApr 10, 2025-
Header (metadata) releaseDec 17, 2025-
Map releaseDec 17, 2025-
UpdateDec 31, 2025-
Current statusDec 31, 2025Processing site: RCSB / Status: Released

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Structure visualization

Supplemental images

emd_70143.png

Downloads & links

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Map

FileDownload / File: emd_70143.map.gz / Format: CCP4 / Size: 178 MB / Type: IMAGE STORED AS FLOATING POINT NUMBER (4 BYTES)
Projections & slices

Image control

Size
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AxesZ (Sec.)Y (Row.)X (Col.)
1.19 Å/pix.
x 360 pix.
= 428.256 Å		1.19 Å/pix.
x 360 pix.
= 428.256 Å		1.19 Å/pix.
x 360 pix.
= 428.256 Å

Surface

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Images are generated by Spider.

Voxel sizeX=Y=Z: 1.1896 Å
Density

Histogram

Histogram (log scale)
Contour LevelBy AUTHOR: 0.03
Minimum - Maximum-0.3232303 - 0.8880616
Average (Standard dev.)0.00033646333 (±0.017241253)
SymmetrySpace group: 1
Details

EMDB XML:

Map geometry
Axis orderXYZ
Origin000
Dimensions360360360
Spacing360360360
CellA=B=C: 428.25598 Å
α=β=γ: 90.0 °

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Supplemental data

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Mask #1

Fileemd_70143_msk_1.map
Projections & Slices
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Additional map: Local map of channel core region.

Fileemd_70143_additional_1.map
AnnotationLocal map of channel core region.
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Additional map: Local map of LRR-PSA region.

Fileemd_70143_additional_2.map
AnnotationLocal map of LRR-PSA region.
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Half map: #2

Fileemd_70143_half_map_1.map
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Half map: #1

Fileemd_70143_half_map_2.map
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Sample components

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Entire : Heterocomplex of SWELL1 and PSA

EntireName: Heterocomplex of SWELL1 and PSA
Components
  • Complex: Heterocomplex of SWELL1 and PSA
    • Protein or peptide: Puromycin-sensitive aminopeptidase
    • Protein or peptide: Volume-regulated anion channel subunit LRRC8A

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Supramolecule #1: Heterocomplex of SWELL1 and PSA

SupramoleculeName: Heterocomplex of SWELL1 and PSA / type: complex / ID: 1 / Parent: 0 / Macromolecule list: all
Source (natural)Organism: Homo sapiens (human)

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Macromolecule #1: Puromycin-sensitive aminopeptidase

MacromoleculeName: Puromycin-sensitive aminopeptidase / type: protein_or_peptide / ID: 1 / Number of copies: 3 / Enantiomer: LEVO / EC number: cytosol alanyl aminopeptidase
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 99.482414 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MAMPEKRPFE RLPADVSPIN YSLCLKPDLL DFTFEGKLEA AAQVRQATNQ IVMNCADIDI ITASYAPEGD EEIHATGFNY QNEDEKVTL SFPSTLQTGT GTLKIDFVGE LNDKMKGFYR SKYTTPSGEV RYAAVTQFEA TDARRAFPCW DEPAIKATFD I SLVVPKDR ...String:
MAMPEKRPFE RLPADVSPIN YSLCLKPDLL DFTFEGKLEA AAQVRQATNQ IVMNCADIDI ITASYAPEGD EEIHATGFNY QNEDEKVTL SFPSTLQTGT GTLKIDFVGE LNDKMKGFYR SKYTTPSGEV RYAAVTQFEA TDARRAFPCW DEPAIKATFD I SLVVPKDR VALSNMNVID RKPYPDDENL VEVKFARTPV MSTYLVAFVV GEYDFVETRS KDGVCVRVYT PVGKAEQGKF AL EVAAKTL PFYKDYFNVP YPLPKIDLIA IADFAAGAME NWGLVTYRET ALLIDPKNSC SSSRQWVALV VGHELAHQWF GNL VTMEWW THLWLNEGFA SWIEYLCVDH CFPEYDIWTQ FVSADYTRAQ ELDALDNSHP IEVSVGHPSE VDEIFDAISY SKGA SVIRM LHDYIGDKDF KKGMNMYLTK FQQKNAATED LWESLENASG KPIAAVMNTW TKQMGFPLIY VEAEQVEDDR LLRLS QKKF CAGGAYVGED CPQWMVPITI STSEDPNQAK LKILMDKPEM NVVLKNVKPD QWVKLNLGTV GFYRTQYSSA MLESLL PGI RDLSLPPVDR LGLQNDLFSL ARAGIISTVE VLKVMEAFVN EPNYTVWSDL SCNLGILSTL LSHTDFYEEI QEFVKDV FS PIGERLGWDP KPGEGHLDAL LRGLVLGKLG KAGHKATLEE ARRRFKDHVE GKQILSADLR SPVYLTVLKH GDGTTLDI M LKLHKQADMQ EEKNRIERVL GATLLPDLIQ KVLTFALSEE VRPQDTVSVI GGVAGGSKHG RKAAWKFIKD NWEELYNRY QGGFLISRLI KLSVEGFAVD KMAGEVKAFF ESHPAPSAER TIQQCCENIL LNAAWLKRDA ESIHQYLLQR KASPPTVTGG LVPR

UniProtKB: Puromycin-sensitive aminopeptidase

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Macromolecule #2: Volume-regulated anion channel subunit LRRC8A

MacromoleculeName: Volume-regulated anion channel subunit LRRC8A / type: protein_or_peptide / ID: 2 / Number of copies: 6 / Enantiomer: LEVO
Source (natural)Organism: Homo sapiens (human)
Molecular weightTheoretical: 95.000328 KDa
Recombinant expressionOrganism: Spodoptera frugiperda (fall armyworm)
SequenceString: MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAAPGPEPT YPNSTILPT PDTGPTGIKY DLDRHQYNYV DAVCYENRLH WFAKYFPYLV LLHTLIFLAC SNFWFKFPRT SSKLEHFVSI L LKCFDSPW ...String:
MIPVTELRYF ADTQPAYRIL KPWWDVFTDY ISIVMLMIAV FGGTLQVTQD KMICLPCKWV TKDSCNDSFR GWAAPGPEPT YPNSTILPT PDTGPTGIKY DLDRHQYNYV DAVCYENRLH WFAKYFPYLV LLHTLIFLAC SNFWFKFPRT SSKLEHFVSI L LKCFDSPW TTRALSETVV EESDPKPAFS KMNGSMDKKS STVSEDVEAT VPMLQRTKSR IEQGIVDRSE TGVLDKKEGE QA KALFEKV KKFRTHVEEG DIVYRLYMRQ TIIKVIKFIL IICYTVYYVH NIKFDVDCTV DIESLTGYRT YRCAHPLATL FKI LASFYI SLVIFYGLIC MYTLWWMLRR SLKKYSFESI REESSYSDIP DVKNDFAFML HLIDQYDPLY SKRFAVFLSE VSEN KLRQL NLNNEWTLDK LRQRLTKNAQ DKLELHLFML SGIPDTVFDL VELEVLKLEL IPDVTIPPSI AQLTGLKELW LYHTA AKIE APALAFLREN LRALHIKFTD IKEIPLWIYS LKTLEELHLT GNLSAENNRY IVIDGLRELK RLKVLRLKSN LSKLPQ VVT DVGVHLQKLS INNEGTKLIV LNSLKKMANL TELELIRCDL ERIPHSIFSL HNLQEIDLKD NNLKTIEEII SFQHLHR LT CLKLWYNHIA YIPIQIGNLT NLERLYLNRN KIEKIPTQLF YCRKLRYLDL SHNNLTFLPA DIGLLQNLQN LAITANRI E TLPPELFQCR KLRALHLGNN VLQSLPSRVG ELTNLTQIEL RGNRLECLPV ELGECPLLKR SGLVVEEDLF NTLPPEVKE RLWRADKEQA TGGLVPR

UniProtKB: Volume-regulated anion channel subunit LRRC8A

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Experimental details

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Structure determination

Methodcryo EM
Processingsingle particle reconstruction
Aggregation stateparticle

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Sample preparation

Concentration3.5 mg/mL
BufferpH: 7.5 / Component - Concentration: 150.0 mM / Component - Formula: NaCl / Component - Name: sodium chloride / Details: 20 mM Tris-HCl pH 7.5, 150 mM NaCl, 0.03% GDN
VitrificationCryogen name: ETHANE / Chamber humidity: 100 % / Chamber temperature: 277 K / Instrument: FEI VITROBOT MARK IV

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Electron microscopy

MicroscopeTFS GLACIOS
Image recordingFilm or detector model: FEI FALCON IV (4k x 4k) / Average electron dose: 40.0 e/Å2
Electron beamAcceleration voltage: 200 kV / Electron source: FIELD EMISSION GUN
Electron opticsIllumination mode: FLOOD BEAM / Imaging mode: BRIGHT FIELD / Nominal defocus max: 1.6 µm / Nominal defocus min: 0.6 µm

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Image processing

CTF correctionSoftware - Name: cryoSPARC (ver. 4.6.0) / Type: PHASE FLIPPING AND AMPLITUDE CORRECTION
Startup modelType of model: NONE
Final reconstructionApplied symmetry - Point group: C3 (3 fold cyclic) / Resolution.type: BY AUTHOR / Resolution: 3.19 Å / Resolution method: FSC 0.143 CUT-OFF / Software - Name: cryoSPARC (ver. 4.6.0) / Number images used: 240320
Initial angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.0)
Final angle assignmentType: MAXIMUM LIKELIHOOD / Software - Name: cryoSPARC (ver. 4.6.0)
FSC plot (resolution estimation)

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