Abstract
BackgroundManually finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed. The unclear evolutionary relationship between classical mammalian lipases and the recently discovered human adipose triglyceride lipase (ATGL; a patatin family member) is an exemplary case for such a problem.ResultsWe describe an unsupervised, sensitive sequence segment collection heuristic suitable for assembling very large protein families. It is based on fan-like expanding, iterative database searches. To prevent inclusion of unrelated hits, additional criteria are introduced: minimal alignment length and overlap with starting sequence segments, finding starting sequences in reciprocal searches, automated filtering for compositional bias and repetitive patterns. This heuristic was implemented as FAMILYSEARCHER in the ANNIE sequence analysis environment and applied to search for protein links between the classical lipase family and the patatin-like group.ConclusionThe FAMILYSEARCHER is an efficient tool for tracing distant evolutionary relationships involving large protein families. Although classical lipases and ATGL have no obvious sequence similarity and differ with regard to fold and catalytic mechanism, homology links detected with FAMILYSEARCHER show that they are evolutionarily related. The conserved sequence parts can be narrowed down to an ancestral core module consisting of three β-strands, one α-helix and a turn containing the typical nucleophilic serine. Moreover, this ancestral module also appears in numerous enzymes with various substrate specificities, but that critically rely on nucleophilic attack mechanisms.
Highlights
Finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed
We present sequence-analytic evidence that the adipose triglyceride lipase (ATGL)/patatin family and the classic mammalian lipases represented by the human pancreatic lipase evolved from a common ancestor
Confirming an evolutionary relationship between classical lipases clustered around pancreatic lipase and the ATGL/patatin group is a difficult task because the relationship is distant, the similarity is subtle and the respective common region involves a substructure interrupted with insertions
Summary
Finding subtle yet statistically significant links to distantly related homologues becomes practically impossible for very populated protein families due to the sheer number of similarity searches to be invoked and analyzed. On the other hand considering the historic successes in deciphering the underlying biochemical pathways, it is assumed that the chemical transformation steps of basic metabolites are known in their entirety. This view is seriously questioned in light of the recent discovery of ATGL, a protein that catalyzes the initial step of hydrolysis of triacylglycerides at the surface of lipid droplets in adipocytes [1]. Just considering the many dozens of additional hypothetical human protein sequences with low but statistically significant sequence-similarity to known metabolic enzymes that can be collected with PSI-BLAST searches [4], more such findings are still expected to be ahead. Other lipases, such as hormone sensitive lipase or lipoprotein lipase, are involved in lipid accumulation and release in tissue [7,8]
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