Structural comparison and classification of alpha-helical transmembrane domains based on helix interaction patterns

Angelika Fuchs, Dmitrij Frishman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations


Structural classification of membrane proteins is still in its infancy due to the relative paucity of available three-dimensional structures compared with soluble proteins. However, recent technological advances in protein structure determination have led to a significant increase in experimentally known membrane protein folds, warranting exploration of the structural universe of membrane proteins. Here, a new and completely membrane protein specific structural classification system is introduced that classifies α-helical membrane proteins according to common helix architectures. Each membrane protein is represented by a helix interaction graph depicting transmembrane helices with their pairwise interactions resulting from individual residue contacts. Subsequently, proteins are clustered according to similarities among these helix interaction graphs using a newly developed structural similarity score called HISS. As HISS scores explicitly disregard structural properties of loop regions, they are more suitable to capture conserved transmembrane helix bundle architectures than other structural similarity scores. Importantly, we are able to show that a classification approach based on helix interaction similarity closely resembles conventional structural classification databases such as SCOP and CATH implying that helix interactions are one of the major determinants of α-helical membrane protein folds. Furthermore, the classification of all currently available membrane protein structures into 20 recurrent helix architectures and 15 singleton proteins demonstrates not only an impressive variability of membrane helix bundles but also the conservation of common helix interaction patterns among proteins with distinctly different sequences.

Original languageEnglish
Pages (from-to)2587-2599
Number of pages13
JournalProteins: Structure, Function and Bioinformatics
Issue number12
StatePublished - Sep 2010
Externally publishedYes


  • Helix bundles
  • Membrane proteins
  • Structural classification
  • Structural similarity
  • Structure prediction


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