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Möhlis, K. ; Useini, A. ; Betat, H.* ; Bonin, S.* ; Broghammer, H. ; Nuwayhid, R.* ; Langer, S.* ; Mörl, M.* ; Sträter, N.* ; Heiker, J.T.

Vaspin identified as a DNA-binding serpin with functional consequences for protease inhibition.

FEBS J., DOI: 10.1111/febs.70270 (2025)
Verlagsversion DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
Vaspin is highly expressed not only in the skin but also in the liver and adipose tissue. It counteracts inflammation and oxidative stress in inflammatory skin diseases, obesity, and associated metabolic disorders, in part by inhibiting the kallikrein proteases KLK7 and KLK14. Vaspin binds the cell-surface low-density lipoprotein receptor-related protein 1 (LRP1) with nanomolar affinity, and is rapidly internalized into adipocytes and other cells. We found intracellular vaspin partially localized in the nucleus. Since vaspin binds heparin and inorganic polyphosphates, we investigated the DNA binding of vaspin. Using DNA-affinity chromatography and differential radial capillary action of ligand assays, we found high-affinity binding to random sequences of single- and double-stranded DNA for both vaspin and KLK7. Furthermore, KLK7 inhibition was accelerated fivefold in the presence of DNA molecules at least 40 bases in length. We previously identified the heparin-binding site at a basic patch on the central beta-sheet A of vaspin. In the current work, we determined the crystal structure of polyphosphate P45-bound vaspin, which confirmed previously identified residues mutated to generate a nonheparin-binding (NHB) vaspin variant. While NHB vaspin failed to bind heparin and polyP45, it still bound DNA with high affinity and accelerated protease inhibition. Mutation of closely spaced basic residues in helix A and helix G did not significantly alter DNA binding. In conclusion, we have identified vaspin as the second human DNA-binding serpin. While the exact mode of the nonspecific interaction remains unclear, it accelerates protease inhibition and likely contributes to the nuclear localization observed for internalized vaspin and may allow for intracellular effects.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Dna ; Adipocytes ; Nucleus ; Polyphosphate ; Serpin; Adipose-tissue; Beta-sheet; Alpha-1-antichymotrypsin; Obesity; Ligand; Ment; Alpha(1)-antichymotrypsin; Apoptosis; Residues; Cells
Sprache englisch
Veröffentlichungsjahr 2025
HGF-Berichtsjahr 2025
ISSN (print) / ISBN 1742-464X
e-ISSN 1742-4658
Zeitschrift FEBS Journal, The
Verlag Wiley
Verlagsort 111 River St, Hoboken 07030-5774, Nj Usa
Begutachtungsstatus Peer reviewed
Institut(e) Helmholtz Institute for Metabolism, Obesity and Vascular Research (HI-MAG)
POF Topic(s) 30201 - Metabolic Health
Forschungsfeld(er) Helmholtz Diabetes Center
PSP-Element(e) G-554800-001
Förderungen Studienstiftung des Deutschen Volkes
DOI 10.1111/febs.70270
WOS ID 001574903100001
Scopus ID 105016739741
PubMed ID 40975878
Erfassungsdatum 2025-11-04
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