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- Direct evidence that the N-terminal extensions of the TAP complex act as autonomous interaction scaffolds for the assembly of the MHC I peptide-loading complex (2012)
- The loading of antigenic peptides onto major histocompatibility complex class I (MHC I) molecules is an essential step in the adaptive immune response against virally or malignantly transformed cells. The ER-resident peptide-loading complex (PLC) consists of the transporter associated with antigen processing (TAP1 and TAP2), assembled with the auxiliary factors tapasin and MHC I. Here, we demonstrated that the N-terminal extension of each TAP subunit represents an autonomous domain, named TMD0, which is correctly targeted to and inserted into the ER membrane. In the absence of coreTAP, each TMD0 recruits tapasin in a 1:1 stoichiometry. Although the TMD0s lack known ER retention/retrieval signals, they are localized to the ER membrane even in tapasin-deficient cells. We conclude that the TMD0s of TAP form autonomous interaction hubs linking antigen translocation into the ER with peptide loading onto MHC I, hence ensuring a major function in the integrity of the antigen-processing machinery.
- David gegen Goliath : wie Viren das Immunsystem überlisten (2006)
- Infektionen mit Herpesviren sind bereits seit der Antike bekannt. So beschrieb zum Beispiel schon Hippokrates in seinem »Corpus Hippocraticum« die sich auf der Haut ausbreitenden Herpes Simplex Läsionen und gab der Krankheit ihren bis heute gültigen Namen. Verbürgt ist auch, dass der römische Kaiser Tiberius vor etwa 2000 Jahren während einer auftretenden Herpes labialis-Epidemie das Küssen bei öffentlichen Zeremonien per Dekret verbat. Shakespeare war ebenfalls bestens vertraut mit den periodisch auftretenden Herpes-Bläschen; in seinem Werk »Romeo & Julia« spricht Mercutio zu Romeo: »O’er ladies lips, who straight on kisses dream, which oft the angry Mab with blisters plagues, ….« Doch erst in den 1960er Jahren erkannte man die virale Herkunft der Erkrankung.
- Varicellovirus UL 49.5 proteins differentially affect the function of the transporter associated with antigen processing, TAP (2008)
- Cytotoxic T-lymphocytes play an important role in the protection against viral infections, which they detect through the recognition of virus-derived peptides, presented in the context of MHC class I molecules at the surface of the infected cell. The transporter associated with antigen processing (TAP) plays an essential role in MHC class I–restricted antigen presentation, as TAP imports peptides into the ER, where peptide loading of MHC class I molecules takes place. In this study, the UL49.5 proteins of the varicelloviruses bovine herpesvirus 1 (BHV-1), pseudorabies virus (PRV), and equine herpesvirus 1 and 4 (EHV-1 and EHV-4) are characterized as members of a novel class of viral immune evasion proteins. These UL49.5 proteins interfere with MHC class I antigen presentation by blocking the supply of antigenic peptides through inhibition of TAP. BHV-1, PRV, and EHV-1 recombinant viruses lacking UL49.5 no longer interfere with peptide transport. Combined with the observation that the individually expressed UL49.5 proteins block TAP as well, these data indicate that UL49.5 is the viral factor that is both necessary and sufficient to abolish TAP function during productive infection by these viruses. The mechanisms through which the UL49.5 proteins of BHV-1, PRV, EHV-1, and EHV-4 block TAP exhibit surprising diversity. BHV-1 UL49.5 targets TAP for proteasomal degradation, whereas EHV-1 and EHV-4 UL49.5 interfere with the binding of ATP to TAP. In contrast, TAP stability and ATP recruitment are not affected by PRV UL49.5, although it has the capacity to arrest the peptide transporter in a translocation-incompetent state, a property shared with the BHV-1 and EHV-1 UL49.5. Taken together, these results classify the UL49.5 gene products of BHV-1, PRV, EHV-1, and EHV-4 as members of a novel family of viral immune evasion proteins, inhibiting TAP through a variety of mechanisms.
- Stirb an einem anderen Tag : Virus versus Immunsystem (2009)
- Jeder Mensch kämpft täglich erfolgreich mit Krankheitserregern, ohne dass er sich der komplexen molekularen Vorgänge dabei bewusst wäre. Wie in einem Hollywood-Streifen geht es rasant zur Sache. Ist das Immunsystem angeschlagen oder trifft es auf starke Gegner, kann eine Infektion binnen weniger Tage außer Kontrolle geraten und lebensbedrohliche Reaktionen hervorrufen. Der menschliche Organismus benötigt eine effiziente Verteidigungsstrategie gegen die Eindringlinge und muss, ebenso wie der britische Geheimdienst im Bond-Film, in die Ausbildung geübter Agenten investieren, Agenten mit Doppel-Null-Status. Agenten wie James Bond.
- »Small is beautiful« : Bioforschung in der Nanowelt (2004)
- Im Zuge der steigenden Bedeutung der Proteomforschung und der »Molekularisierung« der Medizin werden neue, effizientere Plattformen zur Untersuchung von Proteinen und deren Wechselwirkungen notwendig. Hier bietet die Nanotechnologie, eine Wissenschaft mit Ursprüngen in der Physik und der Halbleiterindustrie, attraktive Lösungsperspektiven. Ein Bereich der Forschung am Institut für Biochemie der Universität Frankfurt um Prof. Dr. Robert Tampé widmet sich den Aspekten der Nanotechnologie zur Entwicklung von Protein-Chips für die Proteomforschung und Erzeugung von Mustern im Kleinstformat.
- Multicolour fluorescence-detection size-exclusion chromatography for structural genomics of membrane multiprotein complexes (2013)
- Many interesting and important membrane proteins are hetero-oligomeric. However, besides naturally abundant examples, the structures of relatively few such complexes are known. Partly, this is due to difficulties in expression, stoichiometric assembly, and in the evaluation of their stability prior to crystallization trials. Here we describe a new approach, which allows rapid assessment of protein complex quality, assembly and stoichiometry, simplifying the search for conditions conducive to long-term stability and crystallization. Multicolour fluorescence size-exclusion chromatography (MC-FSEC) is used to enable tracking of individual subunits through expression, solubilization and purification steps. We show how the method has been applied to the heterodimeric transporter associated with antigen processing (TAP) and demonstrate how it may be extended in order to analyse membrane multisubunit assemblies.
