A Protein Interaction Network Links GIT1, an Enhancer of Huntingtin Aggregation, to Huntington's Disease
Open accessAbstract
Analysis of protein-protein interactions (PPIs) is a valuable approach for characterizing proteins of unknown function. Here, we have developed a strategy combining library and matrix yeast two-hybrid screens to generate a highly connected PPI network for Huntington's disease (HD). The network contains 186 PPIs among 35 bait and 51 prey proteins. It revealed 165 new potential interactions, 32 of which were confirmed by independent binding experiments. The network also permitted the functional annotation of 16 uncharacterized proteins and facilitated the discovery of GIT1, a G protein-coupled receptor kinase-interacting protein, which enhances huntingtin aggregation by recruitment of the protein into membranous vesicles. Coimmunoprecipitations and immunofluorescence studies revealed that GIT1 and huntingtin associate in mammalian cells under physiological conditions. Moreover, GIT1 localizes to neuronal inclusions, and is selectively cleaved in HD brains, indicating that its distribution and function is altered during disease pathogenesis.
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Y2H has been used to identify potential modulators of Huntington disease, where interactors of huntingtin might modulate disease severity.
“This Y2H approach has also been used to identify potential modulators of Huntington disease166, in which it is thought that inter-actors of huntingtin (the causally mutated pathological protein) might modulate disease severity.”
From Systems biology and gene networks in neurodevelopmental and neurodegenerative disorders (2015) · cites this paper as [166]
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- Authors
- Goehler, H., Lalowski, M., Stelzl, U., Waelter, S., Stroedicke, M., Worm, U., Droege, A., Lindenberg, K. S., Knoblich, M., Haenig, C., Herbst, M., Suopanki, J., Scherzinger, E., Abraham, C., Bauer, B., Hasenbank, R., Fritzsche, A., Ludewig, A. H., Buessow, K., Coleman, S. H., Gutekunst, C.-A., Landwehrmeyer, B. G., Lehrach, H., & Wanker, E. E.
- Affiliations
- Max Delbrück Center (DE)
- Max Planck Institute for Molecular Genetics (DE)
- Universität Ulm (DE)
- Emory University (US)
- Corresponding author
- Wanker, Erich E.
- ORCID
- Venue
- Molecular Cell
- Publisher
- Elsevier BV
- Published
- 2004-09
- Volume
- 15
- Issue
- 6
- Pages
- 853-865
- ISSN
- 1097-2765 (ISSN-L)
- OpenAlex
- W2035595951
- Cited by
- 453
- References
- 52
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 8 · 2023: 4 · 2022: 19 · 2021: 13 · 2020: 10 · 2019: 5 · 2018: 14 · 2017: 19 · 2016: 18 · 2015: 20 · 2014: 28 · 2013: 32 · 2012: 37
- FWCI
- 9.96
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Molecular Cell (publishedVersion)
- PubMed (publishedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- Max Planck Institute for Plasma Physics (submittedVersion)
- Funders
- National Institute of Neurological Disorders and Stroke (NS31862)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Keywords
- GIT1, huntingtin aggregation, Huntington's disease, protein-protein interaction network, yeast two-hybrid screen, neuronal inclusions, proteolytic cleavage, huntingtin
- MeSH terms
- Huntingtin Protein, Amino Acid Sequence, Animals, Antibodies, Monoclonal, Binding Sites, Chlorocebus aethiops, Glutathione, Humans, Huntington Disease, Mice, Transgenic, Nerve Tissue Proteins, Nuclear Proteins, Phosphoproteins, Precipitin Tests, Proline, Protein Binding, Recombinant Fusion Proteins, Tissue Distribution, PC12 Cells, Protein Structure, Tertiary, Cell Cycle Proteins, COS Cells, GTPase-Activating Proteins, Two-Hybrid System Techniques, RNA Interference, Adaptor Proteins, Signal Transducing, Mice, Rats
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