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@ARTICLE{Mhlis:642769,
author = {Möhlis, Kevin and Useini, Abibe and Betat, Heike and
Bonin, Sonja and Broghammer, Helen and Nuwayhid, Rima and
Langer, Stefan and Mörl, Mario and Sträter, Norbert and
Heiker, John T.},
title = {{V}aspin identified as a {DNA} ‐binding serpin with
functional consequences for protease inhibition},
journal = {The FEBS journal},
volume = {NN},
issn = {0014-2956},
address = {Oxford [u.a.]},
publisher = {Wiley-Blackwell},
reportid = {PUBDB-2025-05618},
pages = {NN},
year = {2025},
note = {OnlineFirst VDB},
abstract = {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.},
cin = {EMBL-User},
ddc = {610},
cid = {I:(DE-H253)EMBL-User-20120814},
pnm = {6G3 - PETRA III (DESY) (POF4-6G3) / SFB 1052 C07 -
Molekulare Mechanismen der Vaspin-KLK7 Achse bei Adipositas
und Diabetes (C07) (250084214) / SFB 1052 Z06 -
Identifizierung und molekulare Charakterisierung von
potentiellen Adipositas-Pharmakotherapien (Z06*)
(465387892)},
pid = {G:(DE-HGF)POF4-6G3 / G:(GEPRIS)250084214 /
G:(GEPRIS)465387892},
experiment = {EXP:(DE-H253)P-P14-20150101},
typ = {PUB:(DE-HGF)16},
doi = {10.1111/febs.70270},
url = {https://bib-pubdb1.desy.de/record/642769},
}