% IMPORTANT: The following is UTF-8 encoded. This means that in the presence % of non-ASCII characters, it will not work with BibTeX 0.99 or older. % Instead, you should use an up-to-date BibTeX implementation like “bibtex8” or % “biber”. @ARTICLE{Schumann:1021663, author = {Schumann, Wibke and Loschwitz, Jennifer and Reiners, Jens and Degrandi, Daniel and Legewie, Larissa and Stühler, Kai and Pfeffer, Klaus and Poschmann, Gereon and Smits, Sander H. J. and Strodel, Birgit}, title = {{I}ntegrative modeling of guanylate binding protein dimers}, journal = {Protein science}, volume = {32}, number = {12}, issn = {0961-8368}, address = {Bethesda, Md.}, publisher = {Protein Society}, reportid = {FZJ-2024-00919}, pages = {e4818}, year = {2023}, abstract = {Guanylate-binding proteins (GBPs) are essential interferon-γ-activated largeGTPases that play a crucial role in host defense against intracellular bacteriaand parasites. While their protective functions rely on protein polymerization,our understanding of the structural intricacies of these multimerized statesremains limited. To bridge this knowledge gap, we present dimer models forhuman GBP1 (hGBP1) and murine GBP2 and 7 (mGBP2 and mGBP7) usingan integrative approach, incorporating the crystal structure of hGBP1's GTPasedomain dimer, crosslinking mass spectrometry, small-angle X-ray scattering,protein–protein docking, and molecular dynamics simulations. Our investiga-tion begins by comparing the protein dynamics of hGBP1, mGBP2, andmGBP7. We observe that the M/E domain in all three proteins exhibits signifi-cant mobility and hinge motion, with mGBP7 displaying a slightly less pro-nounced motion but greater flexibility in its GTPase domain. These dynamicdistinctions can be attributed to variations in the sequences of mGBP7 andhGBP1/mGBP2, resulting in different dimerization modes. Unlike hGBP1 andits close ortholog mGBP2, which exclusively dimerize through their GTPasedomains, we find that mGBP7 exhibits three equally probable alternativedimer structures. The GTPase domain of mGBP7 is only partially involved inits dimerization, primarily due to an accumulation of negative charge, allowingmGBP7 to dimerize independently of GTP. Instead, mGBP7 exhibits a strong tendency to dimerize in an antiparallel arrangement across its stalks. Theresults of this work go beyond the sequence–structure–function relationship,as the sequence differences in mGBP7 and mGBP2/hGBP1 do not lead to dif-ferent structures, but to different protein dynamics and dimerization. The dis-tinct GBP dimer structures are expected to encode specific functions crucial fordisrupting pathogen membranes.}, cin = {IBI-7}, ddc = {610}, cid = {I:(DE-Juel1)IBI-7-20200312}, pnm = {5241 - Molecular Information Processing in Cellular Systems (POF4-524)}, pid = {G:(DE-HGF)POF4-5241}, typ = {PUB:(DE-HGF)16}, UT = {WOS:001120921400001}, doi = {10.1002/pro.4818}, url = {https://juser.fz-juelich.de/record/1021663}, }