Extra-Membrane Domains of Membrane Proteins

  Of the membrane proteins of known structure, we found that a remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure. Moreover, 41% of known water soluble protein structures share a domain with an already known membrane protein structure. We also found that functional residues are frequently conserved between extramembrane domains of membrane and soluble proteins that share structural similarity. These results suggest membrane and soluble proteins readily exchange domains and their attendant functionalities. The exchanges between membrane and soluble proteins are particularly frequent in eukaryotes, indicating that this is an important mechanism for increasing functional complexity. The high level of structural overlap between the two classes of proteins provides an opportunity to employ the extensive information on soluble proteins to illuminate membrane protein structure and function, for which much less is known. To this end, we employed structure guided sequence alignment to elucidate the functions of membrane proteins in the human genome. Our results bridge the gap of fold space between membrane and water soluble proteins and provide a resource for the prediction of membrane protein function. A database of predicted structural and functional relationships for proteins in the human genome is provided at sbi.postech.ac.kr/emdmp.



A remarkable 67% of the water soluble domains are structurally similar to water soluble proteins of known structure.



Shared domains between membrane and soluble proteins




Functional residues conserved between membrane and soluble proteins

 

References
Nam H-J, Han SK, Bowie JU, Kim S (2013) Rampant Exchange of the Structure and Function of Extramembrane Domains between Membrane and Water Soluble Proteins. PLoS Comput Biol 9(3): e1002997. doi:10.1371/journal.pcbi.1002997    PubMed    PDF

 

Structure dataset

Structure comparisons


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Human membrane protein sequences

Structure-guided sequence alignment

Conserved functional residues between MPs and SPs

Figures and Tables


  • Figure 1. Analyses of the structural alignments between MPs and SPs
  • Figure 2. Structurally aligned pairs of MPs and SPs
  • Figure 3. Phylogenetic and function enrichment analysis of the structure pairs of MPs and SPs
  • Figure 4. Shared domains between MPs and SPs
  • Figure 5. Functional residues conserved between MPs and SPs
  • Figure 6. Training process of secondary structure element score to separate similar and dissimilar structure pairs between MPs and SPs

  • Supplementary Figure 1. Comparison of structure superimposition by TM-align and other tools.
  • Supplementary Figure 2. Structurally aligned membrane proteins after removing redundant sequences at a threshold of 30% sequence identity.
  • Supplementary Figure 3. Web-server for the structure alignment of membrane and soluble proteins.
  • Supplementary Figure 4. Aligned lengths of the extramembrane domains located at the outside and inside regions of membrane proteins.
  • Supplementary Figure 5. Membrane distances of extramembrane domains with or without soluble counterparts.
  • Supplementary Figure 6. Difference of sequence similarity scores between the first/second shell residues and the rest of the functional residues.
  • Supplementary Figure 7. Sequence similarity scores of the first and second shell residues around the functional sites.
  • Supplementary Figure 8. Functional annotations of the structurally aligned membrane and soluble protein that share conserved functional residues.
  • Supplementary Figure 9. Shared SCOP folds of membrane and soluble proteins.
  • Supplementary Figure 10. Fraction of membrane protein families that share extramembrane domains with soluble counterparts.
  • Supplementary Figure 11. Probability of finding structure pairs with RMSD < 5Ă…and aligned length > 100 residues by SSEA scores.
  • Supplementary Figure 12. Procedure for structure-guided sequence alignment.
  • Supplementary Figure 13. Alignment of secondary structure elements and functional residues between monoacylglycerol lipase ABHD6 and epoxide hydrolase 2.
  • Supplementary Figure 14. Phylogenetic profiles of membrane and soluble proteins that share extramembrane domains.
  • Supplementary Figure 15. Procedure for the structure alignment of membrane and soluble proteins.
  • Supplementary Figure 16. Comparison of structure-guided sequence alignment results by SSEA and HHpred.

  • Supplementary Table 1. Fold types of similar structure pairs between membrane and soluble proteins.
  • Supplementary Table 2. GO enrichment of membrane proteins that have not exchanged domains with soluble proteins.
  • Supplementary Table 3. Sequence similarity scores of the first and second shell residues around common functional sites.
  • Supplementary Table 4. Functional annotation of membrane and soluble protein domains that share conserved functional residues.
  • Supplementary Table 5. Common SCOP folds shared by membrane and soluble proteins.
  • Supplementary Table 6. SwissProt domains of membrane proteins that share sequence similarity with soluble proteins.