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Title: Charged residues next to transmembrane regions revisited: “Positive-inside rule” is complemented by the “negative inside depletion/outside enrichment rule”
Authors: Baker, James Alexander
Wong, Wing-Cheong
Eisenhaber, Birgit
Warwicker, Jim
Eisenhaber, Frank
Keywords: Amino Acid Distribution
Genome-wide Statistical Study
Issue Date: 2017
Source: Baker, J. A., Wong, W.-C., Eisenhaber, B., Warwicker, J., & Eisenhaber, F. (2017). Charged residues next to transmembrane regions revisited: “Positive-inside rule” is complemented by the “negative inside depletion/outside enrichment rule”. BMC Biology, 15(1), 66-.
Series/Report no.: BMC Biology
Abstract: Background: Transmembrane helices (TMHs) frequently occur amongst protein architectures as means for proteins to attach to or embed into biological membranes. Physical constraints such as the membrane’s hydrophobicity and electrostatic potential apply uniform requirements to TMHs and their flanking regions; consequently, they are mirrored in their sequence patterns (in addition to TMHs being a span of generally hydrophobic residues) on top of variations enforced by the specific protein’s biological functions. Results: With statistics derived from a large body of protein sequences, we demonstrate that, in addition to the positive charge preference at the cytoplasmic inside (positive-inside rule), negatively charged residues preferentially occur or are even enriched at the non-cytoplasmic flank or, at least, they are suppressed at the cytoplasmic flank (negative-not-inside/negative-outside (NNI/NO) rule). As negative residues are generally rare within or near TMHs, the statistical significance is sensitive with regard to details of TMH alignment and residue frequency normalisation and also to dataset size; therefore, this trend was obscured in previous work. We observe variations amongst taxa as well as for organelles along the secretory pathway. The effect is most pronounced for TMHs from single-pass transmembrane (bitopic) proteins compared to those with multiple TMHs (polytopic proteins) and especially for the class of simple TMHs that evolved for the sole role as membrane anchors. Conclusions: The charged-residue flank bias is only one of the TMH sequence features with a role in the anchorage mechanisms, others apparently being the leucine intra-helix propensity skew towards the cytoplasmic side, tryptophan flanking as well as the cysteine and tyrosine inside preference. These observations will stimulate new prediction methods for TMHs and protein topology from a sequence as well as new engineering designs for artificial membrane proteins.
DOI: 10.1186/s12915-017-0404-4
Schools: School of Computer Science and Engineering 
Rights: © 2017 Eisenhaber et al. Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.
Fulltext Permission: open
Fulltext Availability: With Fulltext
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