Mechanism of activation and regulation of Deubiquitinase activity in MINDY1 and MINDY2

Of the eight distinct polyubiquitin (polyUb) linkages that can be assembled, the roles of K48-linked polyUb (K48-polyUb) are the most established, with K48-polyUb modified proteins being targeted for degradation. MINDY1 and MINDY2 are members of the MINDY family of deubiquitinases (DUBs) that have exquisite specificity for cleaving K48-polyUb, yet we have a poor understanding of their catalytic mechanism. Here, we analyze the crystal structures of MINDY1 and MINDY2 alone and in complex with monoUb, di-, and penta-K48-polyUb, identifying 5 distinct Ub binding sites in the catalytic domain that explain how these DUBs sense both Ub chain length and linkage type to cleave K48-polyUb chains. The activity of MINDY1/2 is inhibited by the Cys-loop, and we find that substrate interaction relieves autoinhibition to activate these DUBs. We also find that MINDY1/2 use a non-canonical catalytic triad composed of Cys-His-Thr. Our findings highlight multiple layers of regulation modulating DUB activity in MINDY1 and MINDY2

Utilization of Staphylococcal Immune Evasion Protein Sbi as a Novel Vaccine Adjuvant

<p>Co-ligation of the B cell antigen receptor with complement receptor 2 on B-cells via a C3d-opsonised antigen complex significantly lowers the threshold required for B cell activation. Consequently, fusions of antigens with C3d polymers have shown great potential in vaccine design. However, these linear arrays of C3d multimers do not mimic the natural opsonisation of antigens with C3d. Here we investigate the potential of using the unique complement activating characteristics of Staphylococcal immune-evasion protein Sbi to develop a pro-vaccine approach that spontaneously coats antigens with C3 degradation products in a natural way. We show that Sbi rapidly triggers the alternative complement pathway through recruitment of complement regulators, forming tripartite complexes that act as competitive antagonists of factor H, resulting in enhanced complement consumption. These functional results are corroborated by the structure of the complement activating Sbi-III-IV:C3d:FHR-1 complex. Finally, we demonstrate that Sbi, fused with Mycobacterium tuberculosis antigen Ag85b, causes efficient opsonisation with C3 fragments, thereby enhancing the immune response significantly beyond that of Ag85b alone, providing proof of concept for our pro-vaccine approach.</p

The impact of Generation Y on management structures

Die hier vorliegende Bachelorarbeit beschäftigt sich mit der Frage in wie weit sich aktuelle Veränderungen auf die Führung von Unternehmen auswirken. Im Fokus steht hierbei der Einfluss der Digitalisierung und Globalisierung auf bestehende Strukturen und die daraus neu entwickelte Idee von Arbeit durch die Generation Y. Im zweiten Teil der Arbeit wird untersucht ob die Soziokratie ein zukunftsfähiges Konzept der Unternehmensführung ist

A beginner's guide to solution small-angle X-ray scattering (SAXS)

The Beginner's Guide series covers key techniques and offers the scientifically literate but not necessarily expert audience a background briefing on the underlying science of a technique that is (or will be) widely used in molecular bioscience. The series covers a mixture of techniques, including some that are well established amongst a subset of our readership but not necessarily familiar to those in different specialisms. This Beginner's Guide introduces solution small-angle X-ray scattering (SAXS). Solution small-angle X-ray scattering (SAXS) is a powerful technique, which is complementary to different bioanalytical and structural methods. With straightforward data collection procedures and minimal restrictions in sample environment, information on size, shape and conformational flexibility of biological macromolecules and complexes in near native solutions can be rapidly obtained. Here, we highlight the recent developments that have advanced SAXS to a versatile tool with the capability to enrich almost any biochemical study