Research Report 2010 - MDC

projects/ard/] to detect repeats like HEAT, Armadillo,and PBS, that form similar structures composed ofalpha-helices (which we termed alpha-rods) (Palidworet al., 2009). This method allowed us to detect novelinstances of this structure, for example in human proteinsSTAG1-3, SERAC1, and PSMD1-2 & 5. Application ofthe method to human huntingtin and comparison toorthologs allowed us to delimit three alpha-rods inhuntingtin (See Figure 1) whose intra-molecular interactionswe characterized experimentally using yeasttwo hybrid and co-immunoprecipitation of proteinfragments encoding the domains.Protein domain analysisSome of our work focuses on the search for particularprotein functions using protein sequence comparisonand other bioinformatics tools. A recent example is oursearch for proteins regulating mitochondrial morphologywhere we did a computational screen for proteinsequences predicted as mitochondrial and containingRING domains (characteristic of ubiquitinatingenzymes). We experimentally characterized one ofthem, which we named MAPL (mitochondrial anchoredprotein ligase), which is located in the outer membraneof the mitochondria. Observation of MAPL-YFP led tothe first observation of mitochondrially derived vesicles,which fuse with peroxisomes. The protein containsa domain that we named BAM (Besides a Membrane)(Andrade-Navarro et al., 2009), which presents a complicatedtaxonomic distribution, being scattered inarchaea and bacteria, and present in most eukarya (butnot in fungi). We deduce that this domain has beengenerated along the eukaryotic lineage and has beenhorizontally transferred multiple times to and betweenprokaryotic lineages. We hypothesize that it must havea function that confers prokaryotes with a selectiveadvantage without being crucial.Data and text miningDatabases of molecular sequences are a very usefulsource of functional information for genes and proteinsbut nevertheless they are often incomplete or not up todate. This motivates us and many others working in thefield of computational biology to develop tools that“mine” resources that contain textual descriptions ofresearch results, chiefly, the millions of abstracts referringto the biomedical literature deposited in the MED-LINE database. In this respect, we recently developed ascoring system to rank all abstracts in MEDLINE accordingto a training set that can consist of ten of thousandsof abstracts (Fontaine et al., 2009); this is usefulUsing a computational method on a sequence alignment of huntingtinwith its orthologs (output in the background) we predicted thatthe human huntingtin contains three elongated domains (alpha-rods,yellow cylinders), which are involved in intra-molecular (left) and intermolecular(right) interactions, liberally represented in this cartoon.when a researcher has a small dataset of references ofinterest and wants to find “more of the same”.Algorithms such as neural networks or support vectormachines are too computationally intensive for thistask so we opted for a simpler solution that could bedefined as text indexing. We implemented andevaluated this method using a linear naïve Bayesianclassifier in a web server [MedlineRanker; http://cbdm.mdc-berlin.de/~medlineranker/]. This tool usesas input a set of MEDLINE abstracts and optionally abackground to compare to, and outputs discriminatewords and scored abstracts.Selected PublicationsAndrade-Navarro, MA, Sanchez-Pulido, L , McBride, HM. (2009).Mitochondrial vesicles: an ancient process providing new links toperoxisomes. Current Opinion in Cell Biology. 21:560-567.Jean-Fred Fontaine, Adriano Barbosa-Silva, Martin Schaefer, Matthew R.Huska, Enrique M. Muro, and Miguel A. Andrade-Navarro (2009).MedlineRanker: flexible ranking of biomedical literature. Nucl. Acids Res.2009 37: W141-W146.Palidwor, GA, Shcherbinin, S, Huska, MR, Rasko, T, Stelzl, U, Arumughan, A,Foulle, R, Porras, P, Sanchez-Pulido, L, Wanker, EE, Andrade-Navarro, MA.(2009). Detection of alpha-rod repeats using a neural network andapplication to huntingtin. PLoS Comp. Biol. 5, e1000304.Sandie, R, Palidwor, GA, Huska, MR, Porter, CJ, Krzyzanowski, PM, Muro, EM,Perez-Iratxeta, C, Andrade-Navarro, MA. (2009). Recent developments inStemBase: a tool to study gene expression in human and murine stemcells. BMC Research Notes. 2, 39.Muro, E.M., R. Herrington, S. Janmohamed, C. Frelin, M.A. Andrade-Navarro*, and N.N. Iscove*. (2008). Targeting probes to gene 3'-ends byautomated EST cluster analysis. Proc. Natl. Acad. Sci. 150:20286-20290.*Co-senior authors.Technology Platforms 219