TY  - JOUR
A1  - Mueller, Thomas D.
A1  - Fiebig, Juliane E.
A1  - Weidauer, Stella E.
A1  - Qiu, Li-Yan
A1  - Bauer, Markus
A1  - Schmieder, Peter
A1  - Beerbaum, Monika
A1  - Zhang, Jin-Li
A1  - Oschkinat, Hartmut
A1  - Sebald, Walter
T1  - The Clip-Segment of the von Willebrand Domain 1 of the BMP Modulator Protein Crossveinless 2 Is Preformed
JF  - Molecules
N2  - Bone Morphogenetic Proteins (BMPs) are secreted protein hormones that act as morphogens and exert essential roles during embryonic development of tissues and organs. Signaling by BMPs occurs via hetero-oligomerization of two types of serine/threonine kinase transmembrane receptors. Due to the small number of available receptors for a large number of BMP ligands ligand-receptor promiscuity presents an evident problem requiring additional regulatory mechanisms for ligand-specific signaling. Such additional regulation is achieved through a plethora of extracellular antagonists, among them members of the Chordin superfamily, that modulate BMP signaling activity by binding. The key-element in Chordin-related antagonists for interacting with BMPs is the von Willebrand type C (VWC) module, which is a small domain of about 50 to 60 residues occurring in many different proteins. Although a structure of the VWC domain of the Chordin-member Crossveinless 2 (CV2) bound to BMP-2 has been determined by X-ray crystallography, the molecular mechanism by which the VWC domain binds BMPs has remained unclear. Here we present the NMR structure of the Danio rerio CV2 VWC1 domain in its unbound state showing that the key features for high affinity binding to BMP-2 is a pre-oriented peptide loop.
KW  - bone morphogenetic proteins
KW  - TGF-β superfamily
KW  - BMP antagonist
KW  - protein-protein recognition
KW  - NMR spectroscopy
KW  - von Willebrand type C domain
Y1  - 2013
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-97196
ER  - 
TY  - JOUR
A1  - Thomas, Sarah
A1  - Fiebig, Juliane E.
A1  - Kuhn, Eva-Maria
A1  - Mayer, Dominik S.
A1  - Filbeck, Sebastian
A1  - Schmitz, Werner
A1  - Krischke, Markus
A1  - Gropp, Roswitha
A1  - Mueller, Thomas D.
T1  - Design of glycoengineered IL-4 antagonists employing chemical and biosynthetic glycosylation
JF  - ACS Omega
N2  - Interleukin-4 (IL-4) plays a key role in atopic diseases. It coordinates T-helper cell differentiation to subtype 2, thereby directing defense toward humoral immunity. Together with Interleukin-13, IL-4 further induces immunoglobulin class switch to IgE. Antibodies of this type activate mast cells and basophilic and eosinophilic granulocytes, which release pro-inflammatory mediators accounting for the typical symptoms of atopic diseases. IL-4 and IL-13 are thus major targets for pharmaceutical intervention strategies to treat atopic diseases. Besides neutralizing antibodies against IL-4, IL-13, or its receptors, IL-4 antagonists can present valuable alternatives. Pitrakinra, an Escherichia coli-derived IL-4 antagonist, has been evaluated in clinical trials for asthma treatment in the past; however, deficits such as short serum lifetime and potential immunogenicity among others stopped further development. To overcome such deficits, PEGylation of therapeutically important proteins has been used to increase the lifetime and proteolytic stability. As an alternative, glycoengineering is an emerging strategy used to improve pharmacokinetics of protein therapeutics. In this study, we have established different strategies to attach glycan moieties to defined positions in IL-4. Different chemical attachment strategies employing thiol chemistry were used to attach a glucose molecule at amino acid position 121, thereby converting IL-4 into a highly effective antagonist. To enhance the proteolytic stability of this IL-4 antagonist, additional glycan structures were introduced by glycoengineering utilizing eucaryotic expression. IL-4 antagonists with a combination of chemical and biosynthetic glycoengineering could be useful as therapeutic alternatives to IL-4 neutralizing antibodies already used to treat atopic diseases.
KW  - Interleukin-4 (IL-4)
KW  - atopic diseases
KW  - IL-4 antagonists
KW  - glycoengineering
KW  - biosynthetic glycosylation
KW  - chemical glycosylation
Y1  - 2023
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-350278
SN  - 2470-1343
VL  - 8
IS  - 28
ER  -