- Titel
- Molecular Characterization of Serpin-Recepter Interactions
- Zitierfähige Url:
- https://nbn-resolving.org/urn:nbn:de:bsz:15-qucosa2-991730
- Datum der Einreichung
- 20.05.2025
- Datum der Verteidigung
- 05.09.2025
- Abstract (EN)
- The serine protease inhibitor vaspin (SERPINA12) plays a key role in protecting adipose tissue from inflammation and preserving insulin sensitivity in obesity. Unlike many serpins, vaspin interacts with several ligands in addition to its target proteases. The aim of this thesis was to identify new binding molecules and interaction partners of vaspin, focusing on cell surface receptors, and including studies on receptor binding of antitrypsin (AAT, SERPINA1) and neuroserpin (SERPINI1). First, we found that endocytosed vaspin partially localizes to the nucleus and binds strongly to DNA, which also accelerates the inhibition of KLK7. This identifies vaspin as only the second human DNA-binding serpin. We also crystallized polyphosphate-bound vaspin and confirmed a shared polyphosphate- and heparin-binding site atop of central β-sheet A. Secondly, by investigating internalization of vaspin in detail, we identified the LRP1 as the major endocytosis receptor. LRP1 binding depends on prior contact with extracellular matrix heparan sulfates and is further facilitated by insulin-stimulated LRP1 translocation in mature adipocytes. We found that native and polymerized, but not RCL-cleaved vaspin, are endocytosed and partially targeted for lysosomal degradation. Thirdly, we investigated AAT binding to the glucocorticoid receptor (GR) and other reported receptors, comparing native and oxidized, non-inhibitory AAT variants. We found that both native and oxidized AAT bound the GR, suggesting that oxidized AAT may modulate GR-dependent inflammatory responses. Extending these receptor studies to other AAT variants, neuroserpin, and vaspin, we examined serpin binding to various receptors, focusing on the LDL receptor family and other reported receptors. AAT and oxidized AAT bound similar receptors, confirming our previous results, whereas ZZ-AAT, cleaved AAT and neuroserpin did not bind any of the receptors tested. Interestingly, vaspin bound several LDLR family receptors with high affinity. Together, this thesis provides new insights by expanding vaspin’s molecular repertoire, identifying novel ligands and receptors, highlighted by the detailed investigation of LRP1-mediated endocytosis. It also established that oxidized AAT likely exhibits similar signaling capabilities via GR binding.
- Freie Schlagwörter (EN)
- Vaspin, Serpin, Ligands, Adipocyte
- Klassifikation (DDC)
- 570
- Den akademischen Grad verleihende / prüfende Institution
- Universität Leipzig, Leipzig
- Version / Begutachtungsstatus
- publizierte Version / Verlagsversion
- URN Qucosa
- urn:nbn:de:bsz:15-qucosa2-991730
- Veröffentlichungsdatum Qucosa
- 22.09.2025
- Dokumenttyp
- Dissertation
- Sprache des Dokumentes
- Englisch
- Lizenz / Rechtehinweis
CC BY 4.0