Death Domain database:
A manually curated database of protein-protein interactions for Death Domain Superfamily
The Death domain (DD) superfamily is one of the largest classes of protein interaction modules and plays a pivotal role in the apoptosis, inflammation, necrosis, and immune cell signaling pathways. Critical caspase activating complexes in the apoptosis and inflammation signaling pathways are assembled via the DD superfamily. These domains are also involved in recruiting downstream effectors for immune cell receptor signaling, intracellular pathogen sensing, and response to DNA damage (1-3).
The DD superfamily currently comprises four subfamilies:
- Death domain (DD) subfamily (4)
- Death effector domain (DED) subfamily (5)
- Caspase recruitment domain (CARD) subfamily (6)
- Pyrin domain (PYD) subfamily (7)
The functional and structural similarity is key feature for defining the DD superfamily (4-7). The classification of subfamily in the superfamily is mainly by sequence homology (4-7). (* The sequence-based phylogenetic tree is well introduced by ref. 2). These protein interaction modules are evolutionarily conserved in many multicellular organisms, including Mammals, Drosophila, and Caenorhabditis elegans. In the human genome, there are 37 DDs, 7 DEDs, 33 CARDs, and 22 PYDs (1-3). Due to the fact that apoptosis, inflammation and immune receptor signaling events are associated with various human diseases such as cancer, autoimmunity and many immune disorders, studies in these fields are of great biological importance. Accumulating evidence indicates that interactions within the superfamily are specific and almost all homotypic in that only domains within the same subfamily interact with each other. Since specific protein-protein interactions (PPIs) of the DD superfamily are critical for determining downstream events, the investigation of PPIs among the DD superfamily will facilitate the understanding of the DD superfamily mediated signaling events, such as apoptosis, inflammation, immune cell signaling pathway. Accumulating information on the PPIs in many cellular signaling pathways provides crucial insights into understanding the molecular mechanisms and their related disease processes. Because PPI interfaces have emerged as promising drug targets, there has been substantial progress in developing small molecular compounds that competitively interfere with PPIs (8, 9).
To stimulate future researches among scientists who are interested in the DD superfamily mediated signaling pathway, we have developed the Death Domain Database (http://www.deathdomain.org), a manually curated database that aims to provide comprehensive information on PPIs of human DD superfamily. The current version of the Death Domain Database documents 181 PPI pairs among 99 DDS by curating 311 peer-reviewed publications. The Death Domain Database provides a detailed summary of PPI data, which fits into 3 categories: interaction, characterization, and functional role. Users can find in-depth information specified in the literature on relevant analytical methods, structural information. The Death Domain Database has a user-friendly interface with several helpful features, including a search engine, an interaction map, and a function for cross-referencing useful external databases. Our Death Domain Database will provide a valuable tool to assist in understanding and organizing the molecular interaction network of the DD superfamily.
- Park HH, Lo Y, Lin S, Wang L, Yang JK and Wu H. (2007). The Death Domain Superfamily in Intracellular Signaling of Apoptosis and Inflammation. Annu Rev Immunol. 2007;25:561-86
- Kersse K, Verspurten J, Berghe TV, and Vandenabeele P. (2011) The death-fold superfamily of homotypic interaction motifs. Trends Biochem Sci. 2011 Jul 26
- Reed JC, Doctor KS, and Godzik A. (2004) The domains of apoptosis: a genomics perspective. Sci STKE. 2004 Jun 22;2004(239):re9
- Tartaglia, L.A., Ayres, T.M., Wong, G.H.W., and Goeddel, D.V. (1993) A Novel Domain within the 55 kd TNF Receptor Signals Cell Death. Cell, 74, 845-853.
- Chinnalyan, A.M., O’Rourke, K., Tewari, M., and Dixit, V.M. (1995) FADD, a Novel Death Domain-Containing Protein, Interacts with the Death Domain of Fas and Initiates Apoptosis. Cell, 81, 505-512.
- Hofmann K, Bucher P, and Tschopp J. (1997) The CARD domain: a new apoptotic signalling motif. Trends Biochem. Sci., 22, 155-156.
- Bertin, J., and DiStefano, P.S. (2000) The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ., 7, 1273-1274.
- Ruffner H, Bauer A, and Bouwmeester T (2007) Human protein-protein interaction networks and the value for drug discovery. Drug Discov Today. 2007 Sep;12(17-18):709-16
- Wells JA, and McClendon CL. (2007) Reaching for high-hanging fruit in drug discovery at protein-protein interfaces. Nature. 2007 Dec 13;450(7172):1001-9