Transmembrane helix: simple or complex

Abstract

Transmembrane helical segments (TMs) can be classified into two groups of so-called ‘simple’ and ‘complex’ TMs. Whereas the first group represents mere hydrophobic anchors with an overrepresentation of aliphatic hydrophobic residues that are likely attributed to convergent evolution in many cases, the complex ones embody ancestral information and tend to have structural and functional roles beyond just membrane immersion. Hence, the sequence homology concept is not applicable on simple TMs. In practice, these simple TMs can attract statistically significant but evolutionarily unrelated hits during similarity searches (whether through BLAST- or HMM-based approaches). This is especially problematic for membrane proteins that contain both globular segments and TMs. As such, we have developed the transmembrane helix: simple or complex (TMSOC) webserver for the identification of simple and complex TMs. By masking simple TM segments in seed sequences prior to sequence similarity searches, the false-discovery rate decreases without sacrificing sensitivity. Therefore, TMSOC is a novel and necessary sequence analytic tool for both the experimentalists and the computational biology community working on membrane proteins. It is freely accessible at http://tmsoc.bii.a-star.edu.sg or available for download.

Charged residues next to transmembrane regions revisited: “Positive-inside rule” is complemented by the “negative inside depletion/outside enrichment rule”

“…Simple and complex helices were determined using TMSOC [7]. The complexity class is determined by calculating the hydrophobicity and sequence entropy.…”

Transamidase subunit GAA1/GPAA1 is a M28 family metallo-peptide-synthetase that catalyzes the peptide bond formation between the substrate protein’s omega-site and the GPI lipid anchor’s phosphoethanolamine

“…The concept of simple/complex TM regions can be used to distinguish between mere hydrophobic anchors in the membrane (simple TMs) in contrast to complex TMs that fulfil also other structural and/or functional roles 45 - 47 . With the exception of the Plasmodium falciparum case, all other GAA1/GPAA1 sequences studied (human, fly, worm, yeast, Arabidopsis thaliana , Leishmania , Trypanosoma ) have a least 6 complex TMs (as reported by the TMSOC server 45 ). It was experimentally shown that the GAA1/GPAA1 TM regions (especially the C-terminal one with a conserved proline) are important for binding the GPI lipid anchor in a functionally productive manner to the transamidase complex 41 , 48 .…”

Expansion of the Transporter-Opsin-G protein-coupled receptor superfamily with five new protein families

“…Both proteins B and C have 8 TMS with a 4+4 topology. Only one of the aligned TMSs in the TSUP homolog is classified as simple by TMSOC [30]. Given that we found other lower scoring B-C alignments that involve complex TMSs that fully covered one repeat unit and satisfied all other criteria, we trusted the inference.…”

“…We identified significant alignments between members of the ArsP family and the established TOG families LCT, TSUP, and NiCoT. All aligned TMSs are complex according to the TMSOC program and the classification proposed by Eisenhaber's group [30], decreasing the likelihood of a false positive. Protein OGD29236(B) has 13 TMSs with topology 4+N+4+1 (N = 4), which is apparent from the region that aligns with its homologue in TCDB A8VTI4 (TC: 2.A.119.1.2; Fig 4A) and because the corresponding Pfam domain (PF03773) only covers the first 12 TMSs (Fig 4C).…”

“…Given that we found other lower scoring B-C alignments that involve complex TMSs that fully covered one repeat unit and satisfied all other criteria, we trusted the inference. The hydropathy plot of the B-C [30]. NiCoT, member Q7S3L8(D) (TC: 2.A.52.1.8) and its homolog PHH64764(C) apparently have 3 TMSs in their first repeat unit, based on the identification of hydrophobic peaks.…”