Identifizierung von Interaktionspartnern für HIV-1 Nef und ihre potentielle Relevanz bei der Entwicklung der HIV-assoziierten Demenz
Identifizierung von Interaktionspartnern für HIV-1 Nef und ihre potentielle Relevanz bei der Entwicklung der HIV-assoziierten Demenz
Neuro-Aids as a consequence of infection with human immundeficiency virus (HIV), becomes increasingly important due to considerably more efficient anti-AIDS therapies that result in longer life expectancy. Besides HIV Tat the viral Nef protein is hypothesized to play a role in development of Neuro-A...
Saved in:
Personal Name(s): | Mötter, Jessica (Corresponding author) |
---|---|
Contributing Institute: |
Strukturbiochemie; ISB-3 |
Imprint: |
Jülich
Forschungszentrum Jülich GmbH Zentralbibliothek, Verlag
2010
|
Physical Description: |
VI, 173 S : Ill., graph. Darst |
Dissertation Note: |
Universität Düsseldorf, Diss., 2010 |
ISBN: |
978-3-89336-604-0 |
Document Type: |
Book Dissertation / PhD Thesis |
Research Program: |
ohne Topic |
Series Title: |
Schriften des Forschungszentrums Jülich. Reihe Gesundheit / Health
19 |
Subject (ZB): | |
Publikationsportal JuSER |
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520 | |a Neuro-Aids as a consequence of infection with human immundeficiency virus (HIV), becomes increasingly important due to considerably more efficient anti-AIDS therapies that result in longer life expectancy. Besides HIV Tat the viral Nef protein is hypothesized to play a role in development of Neuro-AIDS. Till today the detailed function of HIV-1 Nef protein in the development of neurological manifestations of an HIV infection is not known. Possibly, Nef could contribute to open the blood-brain barrier by activating matrix metalloproteinase-9 allowing HIV to enter the central nervous system. Furthermore, Nef is known to induce chemokine CCL2/MCP1 expression, which causes infiltration of the brain by monocytes. It is also known that oligodendrocytes initiate vacuolar myelopathy. This is amongst others a disease pattern of HIV associated neuromanifestations. Thus, for elucidation of HIV associated neuromanifestations on the molecular level Nef is an interesting candidate. Aim of the present work was the identification of new cellular interaction partners for HIV-1 Nef protein with a potential role in development of HIV associated dementia (HAD). Knowledge of new brain specific interaction partners of Nef may lead to a better understanding of Nef cellular functions. Use of a modern yeast two-hybrid system yielded succeessful identification of proteins as so far unknown interaction partners of membrane associated Nef. A total of 21 proteins, including 17 membrane proteins, were verified as interaction partners of Nef in the yeast system. Some of them may be relevant for HIV/HAD. B-cell receptor-associated protein 31 (Bcap31) was the second most prevalent hit. The interaction of Nef with Bcap31 could be confirmed with coimmunprecipitation in yeast cells. Furthermore, colocalization in Neuro2A cells in structures at plasma membrane succeeded. The glycoprotein M6B (GPM6B) was the most dominant hit in the screen and its interaction with Nef was characterized in detail in the present work. The interaction of Nef with GPM6B could be verified by coimmunprecipitation from yeast cell extract and pulldown assays using rat brain. Furthermore, Nef and GPM6B colocalized in Neuro2A cells and the relevant binding region in GPM6B could be defined to a 16 amino acid residue region, which is very similar to the Nef-binding region of human CD4. Fluorescence measurements resulted in a submicromolar dissociation constant for this interaction. The results obtained in the present work deliver important contributions for a deeper understanding of Nef’s function in HAD. | ||
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