Формування політичних інститутів в країнах Центральної Азії в умовах незалежності

Останні досягнення і соціально-економічні успіхи країн Центральної Азії, що отримали незалежність з розпадом СРСР ґрунтуються на багатьох чинниках, серед яких, у першу чергу, проведення ефективних економічних реформ, становлення середнього класу і формування зрілого суспільства

Structural insights into the contactin 1 – neurofascin 155 adhesion complex

Cell-surface expressed contactin 1 and neurofascin 155 control wiring of the nervous system and interact across cells to form and maintain paranodal myelin-axon junctions. The molecular mechanism of contactin 1 – neurofascin 155 adhesion complex formation is unresolved. Crystallographic structures of complexed and individual contactin 1 and neurofascin 155 binding regions presented here, provide a rich picture of how competing and complementary interfaces, post-translational glycosylation, splice differences and structural plasticity enable formation of diverse adhesion sites. Structural, biophysical, and cell-clustering analysis reveal how conserved Ig1-2 interfaces form competing heterophilic contactin 1 – neurofascin 155 and homophilic neurofascin 155 complexes whereas contactin 1 forms low-affinity clusters through interfaces on Ig3-6. The structures explain how the heterophilic Ig1-Ig4 horseshoe’s in the contactin 1 – neurofascin 155 complex define the 7.4 nm paranodal spacing and how the remaining six domains enable bridging of distinct intercellular distances.Funding Information: We thank the staff of the DLS beamlines I03 and I24 for help with X-ray diffraction data collection and of beamline B21 for help with SAXS data collection. L.M.P.C. thanks Nick Pearce, Jitse van der Horn, and Gijs van der Schot, for the instructional conversations regarding crystallography. K562 cells were a kind gift from Dr. Bas van Steensel at Netherlands Cancer Institute. This project has received funding from the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program with grant agreement No. 677500 (to B.J.C.J.). D.H.M. acknowledges support from Parents in KIND grant, sponsored by the Kavli Institute of Nanoscience, the Department of Bionanoscience in Delft, and the NWO Spinoza Prize. M.A.d.B. and A.J.R.H. acknowledge support from the Netherlands Organization for Scientific Research (NWO) funding the Netherlands Proteomics Centre through the X-omics Road Map program (project 184.034.019). Publisher Copyright: © 2022, The Author(s).BN/Dimphna Meijer LabBN/Bionanoscienc

Functional Differences of Invariant and Highly Conserved Residues in the Extracellular Domain of the Glycoprotein Hormone Receptors*

Multiple interactions exist between human follicle-stimulating hormone (FSH) and the N-terminal hormone-binding fragment of the human FSH receptor (FSHR) extracellular domain (ECD). Binding of the other human glycoprotein hormones to their cognate human receptors (luteinizing hormone receptor (LHR) and thyroid-stimulating hormone receptor (TSHR)) was expected to be similar. This study focuses on amino acid residues in β-strands 2 (Lys74), 4 (Tyr124, Asn129, and Thr130), and 5 (Asp150 and Asp153) of the FSHR ECD identified in the human FSH·FSHR ECD crystal structure as contact sites with the common glycoprotein hormone α-subunit, and on noncontact residues in β-strands 2 (Ser78) and 8 (Asp224 and Ser226) as controls. These nine residues are either invariant or highly conserved in LHR and TSHR. Mutagenesis and functional characterization of these residues in all three human receptors allowed an assessment of their contribution to binding and receptor activation. Surprisingly, the six reported α-subunit contact residues of the FSHR ECD could be replaced without significant loss of FSH binding, while cAMP signaling potency was diminished significantly with several replacements. Comparative studies of the homologous residues in LHR and TSHR revealed both similarities and differences. The results for FSH/FSHR were analyzed on the basis of the crystal structure of the FSH·FSHR ECD complex, and comparative modeling was used to generate structures for domains, proteins, and complexes for which no structures were available. Although structural information of hormone-receptor interaction allowed the identification of hormone-receptor contact sites, functional analysis of each contact site was necessary to assess its contribution to hormone binding and receptor activation