| dc.contributor.advisor | Wienands, Jürgen Prof. Dr. | |
| dc.contributor.author | Kühn, Julius | |
| dc.date.accessioned | 2015-07-03T09:56:56Z | |
| dc.date.available | 2015-07-03T09:56:56Z | |
| dc.date.issued | 2015-07-03 | |
| dc.identifier.uri | http://hdl.handle.net/11858/00-1735-0000-0022-6043-B | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5167 | |
| dc.identifier.uri | http://dx.doi.org/10.53846/goediss-5167 | |
| dc.language.iso | eng | de |
| dc.rights.uri | http://creativecommons.org/licenses/by-nc-nd/4.0/ | |
| dc.subject.ddc | 570 | de |
| dc.title | Multimolecular adaptor protein complexes in B cell receptor signaling | de |
| dc.type | doctoralThesis | de |
| dc.contributor.referee | Wienands, Jürgen Prof. Dr. | |
| dc.date.examination | 2015-05-28 | |
| dc.description.abstracteng | The activation of B cells is the crucial step of the humoral immune response. This process is controlled by the B cell receptor (BCR) signaling pathway which is initiated by antigen recognition. An elaborated and detailed understanding of this pathway is of great interest given that its misregulation is involved in the genesis of leukemia and immunodeficiencies. The adaptor protein SLP65 is a key regulator in BCR signaling. After phosphorylation of its tyrosine residues, SLP65 serves as assembly site for enzymes and facilitates their mutual activation. The activation of SLP65 by phosphorylation is a multi-step process that requires SH3 domain-binding proline motifs within SLP65. These motifs mediate the interaction of SLP65 with the adaptor protein CIN85. While it was known at the beginning of my doctoral thesis project that the SLP65-CIN85 interaction supports the function of SLP65 in the BCR pathway, the underlying mechanism remained totally unclear. The elucidation of this mechanism constitutes the aim of my doctoral thesis.
By a genetic approach including chimeric proteins I could localize the effector function of CIN85 in its C-terminal coiled-coil (CC) domain. To get insight into the function of the CIN85-CC, I determined the protein interactome of CIN85 by SILAC-based mass spectrometry and investigated membrane lipid binding by biochemical means. Next, I focused on the structure of the CIN85-CC in cooperation with Prof. C. Griesinger's group. By NMR-spectroscopy, we obtained the result that the CIN85-CC forms a stable trimer.
In further genetic experiments, I determined that oligomerization of SLP65 is essential for its function in the BCR signaling pathway. Because CIN85 forms a trimer with nine SLP65 binding sites, it provides the required oligomerization by simultaneous binding of several SLP65 molecules. Furthermore, I found out that the SLP65 N-terminus is a pre-requisite for efficient SLP65 oligomerization. As the N-terminus targets SLP65 to intracellular membranes, I could identify vesicles as the platform for SLP65-oligomerization by CIN85. Because CIN85 and its homolog CD2AP interact with several other proteins in the same manner as with SLP65, this mechanism is likely a general biological principle of action for the CIN85-family adaptor proteins. | de |
| dc.contributor.coReferee | Schwappach, Blanche Prof. Dr. | |
| dc.subject.eng | BCR signaling | de |
| dc.subject.eng | B cell activation | de |
| dc.subject.eng | SLP65 | de |
| dc.subject.eng | BLNK | de |
| dc.subject.eng | CIN85 | de |
| dc.identifier.urn | urn:nbn:de:gbv:7-11858/00-1735-0000-0022-6043-B-3 | |
| dc.affiliation.institute | Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und molekulare Biowissenschaften (GGNB) | de |
| dc.subject.gokfull | Biologie (PPN619462639) | de |
| dc.identifier.ppn | 829049320 | |