This website was produced as an assignment for Genetics 677 at UW-Madison Spring 2009

Protein Domains

In order to assess protein motifs present in huntingtin and to acquire more information into the proteins function, I used the Pfam, SMART, and Prosite databases.  The results were generally uninspired; the search engines did not find any motifs with confidence.  After altering the settings to return results with a greater expect value, I was able to uncover one domain, HEAT, which appeared in all of the search engines.  General information, found on Genecards and Interpro, indicates there is another domain known specifically as Huntingtin, which is similar to HEAT repeats.  

HEAT Domain

Both Smart and Pfam returned results including the HEAT domain.  Pfam showed 7 different possible locations of HEAT domains in the human huntingtin sequence, with E-values ranging from 0.00011 to 35.  Interestingly, Pfam returned no results listed as "significant" under the default search settings.  Even so, I am led to beleive due to the common appearance of HEAT domains in HTT that the motif does have a significant function.  The SMART search confirmed this, identifying a HEAT repeat at position 903-940 with an E-value of 0.0017, which corresponds to the location and lowest E-value found in Pfam.  Prosite returned a graphical depiction of HEAT repeats in the protein sequence, seen below.  Note this represents only the first 1000 amino acids in the sequence.

Image of the HEAT repeat domain from Pfam entry 1f59.   

The relevance HEAT in huntingtin supported by an article published in 1995 describing the role of HEAT in huntingtin (1).  In fact, the H in HEAT corresponds to huntingtin; thus they are intricately tied.  Pfam states HEAT is related to armadillo/beta-catenin like repeats, which indicates its function is tied to protein-protein interactions.  HEAT is commonly found in proteins located in the cytoplasm, which includes huntingtin, as well as the other name-giving motifs elongation factor 3 (EF3), a subunit of protein phosphatase 2A (PP2A) and the yeast protein TOR1.  Further research has indicated that huntingtin contains 10 HEAT repeats.  Thus, my search techniques failed to adequately characterize the protein. Interestingly, different numbers of HEAT repeat domains appear in a SMART analysis of the protein sequence of homologs.  A visualization of these domains in all homologs is seen here.  The varying number of HEAT repeats, although never surmounting two, indicates perhaps the annotation of the domains is not complete.  It appears all organisms should maintain a similar amount of HEAT repeats, since the protein is so highly conserved in these species. 

1.  Bork,P;Andrade,MA.1995.  "HEAT repeats in Huntington's Disease Protein."  Nat Genet.  Oct. 11 (2) 115-6.  doi:10.1038/ng1095-115

Created by Eric Nickels [email protected]       5/9/2009      Genetics 677 Webpage