Medical Bioinformatics: Autoinflammatory, Neurodegenerative, and Viral Diseases

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.

News: A joint BioSapiens-viRgil Workshop on Bioinformatics for Viral Infections was held in Bonn, Germany, on 21-23 September 2005. Press release 1. Press release 2. For more information, please visit http://workshop2005.bioinf.mpi-inf.mpg.de/

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: mario.albrecht@mpi-inf.mpg.de)

Autoinflammatory Diseases

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).

Figures 1 and 2 (click on picture for enlargement)
FIGURE1 FIGURE2

Figures 3 and 4 (click on picture for enlargement)
FIGURE3 FIGURE4

Experimental and Medical Cooperation Partners

References

  1. Schreiber, S., Rosenstiel, P., Albrecht, M., Hampe, J., Krawczak, M.
    Genetics of Crohn disease, an archetypal inflammatory barrier disease.
    Nature Reviews Genetics, 6(5):376-388, 2005.
    (Abstract)
  2. Valentonyte, R., Hampe, J., Huse, K., Rosenstiel, P., Albrecht, M., Stenzel, A., Nagy, M., Gaede, K.I., Franke, A., Haesler, R., Koch, A., Lengauer, T., Seegert, D., Reiling, N., Ehlers, S., Schwinger, E., Platzer, M., Krawczak, M., Muller-Quernheim, J., Schurmann, M., Schreiber, S.
    Sarcoidosis is associated with a truncating splice site mutation in BTNL2.
    Nature Genetics, 37(4):357-364, 2005.
    (Abstract) (Supplement) (Press release 1) (Press release 2)
  3. Costello, C.M., Mah, N., Häsler, R., Rosenstiel, P., Waetzig, G.H., Hahn, A., Lu, T., Gurbuz, Y., Nikolaus, S., Albrecht, M., Hampe, J., Lucius, R., Klöppel, G., Eickhoff, H., Lehrach, H., Lengauer, T., Schreiber, S.
    Dissection of the inflammatory bowel disease transcriptome using genome-wide cDNA microarrays identifies novel candidate disease genes.
    PLoS Medicine, 2(8):e199.1-17, 2005.
    (Abstract) (Synopsis) (Press release)
  4. Albrecht, M., Choubey, D., Lengauer, T.
    The HIN domain of IFI-200 proteins consists of two OB folds.
    Biochemical and Biophysical Research Communications, 327(3):679-687, 2005.
    (Abstract)
  5. Van Duist, M.M., Albrecht, M., Podswiadek, M., Giachino, D., Lengauer, T., Punzi, L., De Marchi, M.
    A new CARD15 mutation in Blau syndrome
    European Journal of Human Genetics, 13(6):742-747, 2005.
    (Abstract)
  6. Stoll, M., Corneliussen, B., Costello, C.M., Waetzig, G.H., Mellgard, B., Koch, W.A., Rosenstiel, P., Albrecht, M., Croucher, P.J.P., Seegert, D., Nikolaus, S., Hampe, J., Lengauer, T., Pierrou, S., Foelsch, U.R., Mathew, C.G., Lagerstrom-Fermer, M., Schreiber, S.
    Genetic variation in DLG5 is associated with inflammatory bowel disease.
    Nature Genetics, 36(5):476-480, 2004.
    (Abstract) (Supplement) (Press release)
  7. Albrecht, M., Domingues, F.S., Schreiber, S., Lengauer, T.
    Structural localization of disease-associated sequence variations in the NACHT and LRR domains of PYPAF1 and NOD2.
    FEBS Letters, 554(3):520-528, 2003.
    (Abstract) (Supplement)
  8. Albrecht, M., Lengauer, T., Schreiber, S.
    Disease-associated variants in PYPAF1 and NOD2 result in similar alterations of conserved sequence.
    Bioinformatics, 19(17):2171-2175, 2003.
    (Abstract)
  9. Albrecht, M., Domingues, F.S., Schreiber, S., Lengauer, T.
    Identification of mammalian orthologs associates PYPAF5 with distinct functional roles.
    FEBS Letters, 538(1-3):173-177, 2003.
    (Abstract) (Supplement)

Neurodegenerative Disorders

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 homologs of ataxin-2 and ataxin-7. 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 important functions of ataxin-2 in RNA metabolism and SH3 domain complexes as well as on the binding mode of ataxin-3 to ubiquitin and the multifunctional ATPase p97/VCP/Cdc48.

Apart from polyglutamine proteins, we could recently point to the putative molecular malfunction of the dardarin protein LRRK2/RIP7 in Parkinsonism based on a structural analysis of its protein kinase domain.

Experimental and Medical Cooperation Partners

References

  1. Ralser, M., Nonhoff, U., Albrecht, M., Lengauer, T., Wanker, E.E., Lehrach, H., Krobitsch, S.
    Ataxin-2 and huntingtin interact with endophilin-A complexes to function in plastin-associated pathways.
    Human Molecular Genetics, 14(19):2893-2909, 2005.
    (Abstract) (Supplement)
  2. Albrecht, M., Huthmacher, C., Tosatto, S.C.E., Lengauer, T.
    Decomposing protein networks into domain-domain interactions.
    Bioinformatics, 21(Suppl. 2):ii220-ii221, 2005.
    (Abstract) (Supplement)
  3. Ralser, M., Albrecht, M., Nonhoff, U., Lengauer, T., Lehrach, H., Krobitsch, S.
    An integrative approach to gain insights into the cellular function of human ataxin-2.
    Journal of Molecular Biology, 346(1):203-214, 2005.
    (Abstract) (Supplement)
  4. Albrecht, M.
    LRRK2 mutations and parkinsonism.
    The Lancet, 365(9466):1230, 2005.
    (Abstract)
  5. Albrecht, M., Golatta, M., Wüllner, U., Lengauer, T.
    Structural and functional analysis of ataxin-2 and ataxin-3.
    European Journal of Biochemistry, 271(15):3155-3170, 2004.
    (Abstract) (Supplement)
  6. Albrecht, M., Lengauer, T.
    Novel Sm-like proteins with long C-terminal tails and associated methyltransferases.
    FEBS Letters, 569(1-3):18-26, 2004.
    (Abstract) (Supplement)
  7. Albrecht, M., Lengauer, T.
    Survey on the PABC recognition motif PAM2.
    Biochemical and Biophysical Research Communications, 316(1):129-138, 2004.
    (Abstract)
  8. Albrecht, M., Hoffmann, D., Evert, B.O., Schmitt, I., Wüllner, U., Lengauer, T.
    Structural modeling of ataxin-3 reveals distant homology to adaptins.
    Proteins: Structure, Function, and Genetics, 50(2):355-370, 2003.
    (Abstract)

Hepatitis C Virus

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: christoph.welsch@mpi-inf.mpg.de) and Mario Albrecht (E-mail: mario.albrecht@mpi-inf.mpg.de)

Experimental and Medical Cooperation Partners

References

  1. Sarrazin, C., Mihm, U., Herrmann, E., Welsch, C., Albrecht, M., Sarrazin, U., Traver, S., Lengauer, T., Zeuzem, S.
    Clinical significance of in vitro-replication enhancing mutations of the hepatitis C virus replicon in patients with chronic hepatitis C.
    Journal of Infectious Diseases, 192, in press, 2005.
  2. Hofmann, W.P., Herrmann, E., Kronenberger, B., Merkwirth, C., Welsch, C., Lengauer, T., Zeuzem, S., Sarrazin, C.
    Association of HCV-related mixed cryoglobulinemia with specific mutational pattern of the HCV E2 protein and CD81 expression on peripheral B lymphocytes.
    Blood, 104(4):1228-1229, 2004.
    (Abstract)
  3. Kronenberger, B., Sarrazin, C., Hofmann, W.P., von Wagner, M., Herrmann, E., Welsch, C., Elez, R., Ruster, B., Piiper, A., Zeuzem, S.
    Mutations in the putative HCV-E2 CD81 binding regions and correlation with cell surface CD81 expression.
    Journal of Viral Hepatitis, 11(4):310-318, 2004.
    (Abstract)
  4. Zeuzem, S., Welsch, C., Herrmann, E.
    Pharmacokinetics of peginterferons.
    Seminars in Liver Disease, 23(Suppl. 1):23-28, 2003.
    (Abstract)