Protein interactions in human genetic diseases - PubMed (original) (raw)

Protein interactions in human genetic diseases

Benjamin Schuster-Böckler et al. Genome Biol. 2008.

Abstract

We present a novel method that combines protein structure information with protein interaction data to identify residues that form part of an interaction interface. Our prediction method can retrieve interaction hotspots with an accuracy of 60% (at a 20% false positive rate). The method was applied to all mutations in the Online Mendelian Inheritance in Man (OMIM) database, predicting 1,428 mutations to be related to an interaction defect. Combining predicted and hand-curated sets, we discuss how mutations affect protein interactions in general.

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Figures

Figure 1

Figure 1

Conservation difference between wild-type and mutated residues. Histogram of conservation of wild-type and mutated residues. Triangles denote the residue-conservation frequency of all residues in disease protein regions that map to an _i_Pfam domain. Circles show the conservation of the pathogenic alleles (see Materials and methods). Trendlines are added to delineate normal distributions.

Figure 2

Figure 2

ROC curves calculated on a set of alanine scanning experiments. The red line represents the performance of our algorithm when changing only the conservation threshold, applying no percentage identity cutoff. The green line shows the performance using only percentage identity as a threshold. The blue line reflects performance using conservation as threshold, but applying a 30% sequence identity filter. Confidence intervals where calculated using the Statistics::ROC Perl module [59].

Figure 3

Figure 3

Data integration steps for interacting residue prediction. Schematic outline of data integration for the prediction of interacting residues. Mutations from OMIM and UniProt for which a residue in a homologous structure is involved in an interaction are selected. This set is restricted further by searching for homologous proteins with known interactions, taken from a range of protein interaction databases. We require that the the homologous interacting proteins contain the same pair of Pfam domains that was observed in the structural template. This results in a set of 1,428 interaction related mutations.

Figure 4

Figure 4

Structure of Rattus norvegicus Ras-related protein Rab-3A [PDB:1ZBD]. The small G protein Rab3A with bound GTP interacting with the effector domain of rabphilin-3A. The residue corresponding to the mutated Trp73 from human RAB27A is highlighted in red, while the two residues in contact with it are coloured green.

Figure 5

Figure 5

Structure of X. laevis Brachyury protein [PDB:1XBR]. The crystal structure of a T-domain from X. laevis bound to DNA. The residues highlighted in red are the mutated Ser128, with green residues representing the contact residues in the partner protein. Blue dashed lines show residue contacts.

Figure 6

Figure 6

Structure of the Myc/Max transcription factor complex binding DNA [PDB:1NKP]. Both Myc-c and Max form a basic helix-loop-helix motif. They dimerize mainly through their extended helix II regions. The residue that corresponds to Ile156 in H-Twist is Ile550, shown in red. The residue sits at a key position of the interface, forming bonds with seven residues in Max, shown in green.

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References

    1. Sharan R, Ideker T. Modeling cellular machinery through biological network comparison. Nat Biotech. 2006;24:427–433. doi: 10.1038/nbt1196. - DOI - PubMed
    1. Gandhi TK, Zhong J, Mathivanan S, Karthick L, Chandrika KN, Mohan SS, Sharma S, Pinkert S, Nagaraju S, Periaswamy B, Mishra G, Nandakumar K, Shen B, Deshpande N, Nayak R, Sarker M, Boeke JD, Parmigiani G, Schultz J, Bader JS, Pandey A. Analysis of the human protein interactome and comparison with yeast, worm and fly interaction datasets. Nat Genet. 2006;38:285–293. doi: 10.1038/ng1747. - DOI - PubMed
    1. Hart GT, Ramani AK, Marcotte EM. How complete are current yeast and human protein-interaction networks? Genome Biol. 2006;7:120. doi: 10.1186/gb-2006-7-11-120. - DOI - PMC - PubMed
    1. Giorgini F, Muchowski PJ. Connecting the dots in Huntington's disease with protein interaction networks. Genome Biol. 2005;6:210. doi: 10.1186/gb-2005-6-3-210. - DOI - PMC - PubMed
    1. Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY. A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration. Cell. 2006;125:801–814. doi: 10.1016/j.cell.2006.03.032. - DOI - PubMed

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