Identification and characterization of subfamily-specific signatures in a large protein superfamily by a hidden Markov model approach.
BACKGROUND
Most profile and motif databases strive to classify protein sequences into a broad spectrum of protein families. The next step of such database studies should include the development of classification systems capable of distinguishing between subfamilies within a structurally and functionally diverse superfamily. This would be helpful in elucidating sequence-structure-function relationships of proteins.


RESULTS
Here, we present a method to diagnose sequences into subfamilies by employing hidden Markov models (HMMs) to find windows of residues that are distinct among subfamilies (called signatures). The method starts with a multiple sequence alignment (MSA) of the subfamily. Then, we build a HMM database representing all sliding windows of the MSA of a fixed size. Finally, we construct a HMM histogram of the matches of each sliding window in the entire superfamily. To illustrate the efficacy of the method, we have applied the analysis to find subfamily signatures in two well-studied superfamilies: the cadherin and the EF-hand protein superfamilies. As a corollary, the HMM histograms of the analyzed subfamilies revealed information about their Ca2+ binding sites and loops.


CONCLUSIONS
The method is used to create HMM databases to diagnose subfamilies of protein superfamilies that complement broad profile and motif databases such as BLOCKS, PROSITE, Pfam, SMART, PRINTS and InterPro.
Truong
Kevin
K
Division of Molecular and Structural Biology, Ontario Cancer Institute and Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada. ktruong@uhnres.utoronto.ca
Ikura
Mitsuhiko
M
D001665:Binding Sites / Q000235:genetics; D015820:Cadherins / Q000737:chemistry / Q000235:genetics; D002135:Calcium-Binding Proteins / Q000737:chemistry / Q000235:genetics; D019295:Computational Biology / Q000379:methods; D030562:Databases, Protein; D020832:EF Hand Motifs / Q000235:genetics; D008390:Markov Chains; D008957:Models, Genetic; D010320:Parvalbumins / Q000737:chemistry / Q000235:genetics; D011506:Proteins / Q000737:chemistry* / Q000235:genetics*; D020543:Proteome / Q000737:chemistry / Q000235:genetics; D040901:Proteomics / Q000379:methods / Q000706:statistics & numerical data; D021281:Quantitative Structure-Activity Relationship; D016415:Sequence Alignment / Q000379:methods
D015820:Cadherins; D002135:Calcium-Binding Proteins; D010320:Parvalbumins; D011506:Proteins; D020543:Proteome