in association with the DFG project PROSTFUN and the BioSapiens European Network of Excellence on protein structure and function prediction
We aim at the development of bioinformatics methods to advance the understanding of disease processes and the effect of genetic variations on protein function and drug therapies. To this end, application studies on structure and function prediction of medically relevant proteins are being conducted in cooperation with research groups from medical institutes associated with NGFN projects on environmental diseases, EUROSCA projects on polyglutamine disorders, and the VIRGIL European Network of Excellence on Hepatitis C.
Current job offer for post-doc/PhD student: Structural and functional analysis of medically relevant proteins and their interaction networks. Interest in biology/medicine and expertise in programming is desired.
Contact: Mario Albrecht (E-mail: firstname.lastname@example.org)
Non-synonymous SNPs in the homologous gene products PYPAF1 and NOD2 have been associated with several autoinflammatory diseases that, although clinically different, share a similar inflammatory pathophysiology.
PYPAF1/CIAS1 has been linked to chronic infantile neurological cutaneous and articular syndrome (CINCA, also known as neonatal-onset multisystem inflammatory disease, NOMID), familial cold autoinflammatory syndrome (FCAS, also called familial urticaria, FCU), and Muckle-Wells syndrome (MWS). NOD2/CARD15 has been found to confer susceptibility to Blau syndrome (BS, also named arthrocutaneouveal granulomatosis, ACUG) and one of the two main types of chronic inflammatory bowel disease (IBD), Crohn's disease (CD). PYPAF1 and NOD2 are both involved in the regulation of inflammatory immune responses.
The comparative analysis of the genetic variations with respect to their structural impact on the protein level gives important insights into disease mechanisms. We assembled multiple sequence alignments of the family members sharing a homologous domain architecture with a central NTPase domain called NACHT and a C-terminal LRR (leucine-rich repeat) domain. Our sequence alignments and 3D structural domain models demonstrate that most of the disease-associated variants are located in highly conserved and spatially adjacent regions of the NACHT domain and possibly impair NTP-hydrolysis or oligomerization (Figures 1 and 2). We could also provide a hypothetical model of the NACHT-LRR domain complex (Figure 3).
Apart from that, our comprehensive computational analysis revealed the mouse orthologs of PYPAF1 and NOD2 and of other human homologs such as NOD1 and PYPAF5. Surprisingly, we found that this discovery associated the family member PYPAF5 with two contradictory functional roles reported previously, as cytosplasmic regulator of inflammatory processes and as transmembrane hormone receptor.
Recently, we could contribute to the analysis of the membrane-associated gyanylate kinase DLG5, which has been associated with IBD, and interferon-inducible IFI-200 proteins, which are transcriptional regulators involved in inflammation and cancer.
Another structural model of the BTNL2 gene product, a butyrophilin-like member of the immmunoglobulin superfamily, supported experimental investigations on the truncating splice site mutation associated with the multisystemic immune disorder sarcoidosis (Figure 4).
Experimental and Medical Cooperation Partners
The proteins ataxin-2 and ataxin-3 are the gene products of the spinocerebellar ataxia type 2 and 3 genes SCA2 and SCA3/MJD. Both proteins contain a polyglutamine tract encoded by CAG repeats. Its expansion beyond a certain threshold causes the associated autosomal-dominantly inherited neurodegenerative disorders.
Both diseases SCA2 and SCA3 belong to a heterogeneous group of trinucleotide repeat disorders, which includes Huntington's disease and several other spinocerebellar ataxia types such as SCA1, SCA7 and SCA10. The disorders share common phenotypical features such as the degeneration of specific vulnerable neuron populations and the presence of intracellular aggregations of the mutant proteins in affected neurons.
To provide a rationale for further experiments, we explored the protein architectures of ataxin-2 and ataxin-3 and the protein interaction networks around other eukaryotic homologs. Using structure-based multiple sequence alignments of homologous proteins, we investigated domains, sequence motifs, and interaction partners. Our analyses focused on functional amino acids and the construction of three-dimensional models of the RNA-binding Lsm (Like Sm) domain of ataxin-2 and the de-ubiquitinating Josephin domain of ataxin-3. Based on our findings, we proposed further experiments on an important function of ataxin-2 in RNA metabolism and on the binding mode of ataxin-3 to the multifunctional ATPase p97/VCP/Cdc48.
Apart from polyglutamine proteins, we could recently point to the putative molecular malfunction of the dardarin protein LRRK2 in Parkinsonism based on a structural analysis of its protein kinase domain.Experimental and Medical Cooperation Partners
Hepatitis C is an important viral disease with about half a million patients in Germany and more than 170 million people affected world-wide. We use bioinformatics means to analyze sequence variations and the structure and function of HCV gene products as well as protein interactions with the human host.
Contacts: Christoph Welsch (E-mail: email@example.com) and Mario Albrecht (E-mail: firstname.lastname@example.org)
Experimental and Medical Cooperation Partners