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

BMC Biology

Research Article

Wing-Cheong Wong¹  Birgit Eisenhaber¹  James Alexander Baker²  Frank Eisenhaber³  Jim Warwicker⁴ 

[1] Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), 30 Biopolis Street #07-01, Matrix, 138671, Singapore, Singapore;Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), 30 Biopolis Street #07-01, Matrix, 138671, Singapore, Singapore;School of Chemistry, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, UK;Bioinformatics Institute, Agency for Science Technology and Research (A*STAR), 30 Biopolis Street #07-01, Matrix, 138671, Singapore, Singapore;School of Computer Engineering (SCE), Nanyang Technological University (NTU), 50 Nanyang Drive, 637553, Singapore, Singapore;School of Chemistry, Manchester Institute of Biotechnology, 131 Princess Street, M1 7DN, Manchester, UK;

关键词: Amino acid distribution;    Genome-wide statistical study;    Membrane protein;    Negative-not-inside/negative-outside rule;    Protein topology prediction;    Proteomics;    Transmembrane helix;    Transmembrane region prediction;   

DOI  :  10.1186/s12915-017-0404-4

 received in 2017-07-03, accepted in 2017-07-07,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundTransmembrane 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.ResultsWith 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.ConclusionsThe 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.

【 授权许可】

CC BY   
© Eisenhaber et al. 2017