Identification of potential drug targets implicated in Parkinson's disease from human genome: insights of using fused domains in hypothetical proteins as probes

Abstract

High-throughput genome sequencing has led to data explosion in sequence databanks, with an imbalance of sequence-structure-function relationships, resulting in a substantial fraction of proteins known as hypothetical proteins. Functions of such proteins can be assigned based on the analysis and characterization of the domains that they are made up of. Domains are basic evolutionary units of proteins and most proteins contain multiple domains. A subset of multidomain proteins is fused domains (overlapping domains), wherein sequence overlaps between two or more domains occur. These fused domains are a result of gene fusion events and their implication in diseases is well established. Hence, an attempt has been made in this paper to identify the fused domain containing hypothetical proteins from human genome homologous to parkinsonian targets present in KEGG database. The results of this research identified 18 hypothetical proteins, with domains fused with ubiquitin domains and having homology with targets present in parkinsonian pathway.

Figure 1

17 clusters in fused hypothetical proteins containing 36 domains.

Figure 2

Parkinson's disease pathway from the KEGG disease database. Proteins encircled with red color are the ones having fused domains with ubiquitin domains (source: the KEGG disease pathway database).

Figure 3

Domains in cluster-1.

Figure 4

Multiple sequence alignment of the fused domains in 6 unique hypothetical proteins and their target sequences (PARK2 and ubiquitin sequence).

Figure 5

PROSITE signature PS00299 comparison in hypothetical sequences for a ubiquitin domain. Square brackets in the signature indicate the presence of either of the residues at that position, whereas the x(3) indicates any three amino acids. The red-colored residue indicates the strictly conserved residues, blue-colored ones indicates the residues present in the regular expression patterns, and the orange-colored ones indicate the mutant residues as observed from the mutant database.

Figure 6

Domains in cluster-2.

Figure 7

Pairwise sequence alignment of the fused domains between the ubiquitin sequence and its homolog hypothetical sequence (gi:12053109).

Figure 8

Domains in cluster-5.

Figure 9

Multiple-sequence alignment of the fused domains in 7 unique hypothetical proteins and PINK1 sequence.

Figure 10

Domains in cluster-8.

Figure 11

Multiple-sequence alignment of the fused domains in 4 unique hypothetical proteins and their target sequence (UBA1).