Abstract
Despite significant methodological advances in protein structure determination high-resolution structures of membrane proteins are still rare, leaving sequence-based predictions as the only option for exploring the structural variability of membrane proteins at large scale. Here, a new structural classification approach for α-helical membrane proteins is introduced based on the similarity of predicted helix interaction patterns. Its application to proteins with known 3D structure showed that it is able to reliably detect structurally similar proteins even in the absence of any sequence similarity, reproducing the SCOP and CATH classifications with a sensitivity of 65% at a specificity of 90%. We applied the new approach to enhance our comprehensive structural classification of α-helical membrane proteins (CAMPS), which is primarily based on sequence and topology similarity, in order to find protein clusters that describe the same fold in the absence of sequence similarity. The total of 151 helix architectures were delineated for proteins with more than four transmembrane segments. Interestingly, we observed that proteins with 8 and more transmembrane helices correspond to fewer different architectures than proteins with up to 7 helices, suggesting that in large membrane proteins the evolutionary tendency to re-use already available folds is more pronounced.
Highlights
Since the determination of the first membrane protein structure in 1985 [1] a lot has changed in our knowledge about the membrane protein structure space
In accordance with the current approach adopted both by SCOP and CATH for transmembrane proteins [13], all proteins were treated as single domain proteins
The obtained classification was compared to the corresponding SCOP/CATH classification of the same proteins as well as to our own HISSdb classification
Summary
Since the determination of the first membrane protein structure in 1985 [1] a lot has changed in our knowledge about the membrane protein structure space. Recent structures have shown that they can be much more complex [4,5,6,7,8,9,10], warranting research on the structural variability of membrane proteins by means of structure classification methods. Our comparative analysis of the structural classification of a-helical membrane proteins in these databases has shown that the fold definition initially developed for globular proteins is applicable to membrane proteins only to a limited degree [13]. We suggested revising the fold definition for membrane proteins by incorporating more fine-grained structural features such as helix-helix interactions
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