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

Content Provider	Springer Nature : BioMed Central
Author	Baker, James Alexander Wong, Wing-Cheong Eisenhaber, Birgit Warwicker, Jim Eisenhaber, Frank
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.
Related Links	https://bmcbiol.biomedcentral.com/counter/pdf/10.1186/s12915-017-0404-4.pdf
Ending Page	29
Page Count	29
Starting Page	1
File Format	HTM / HTML
ISSN	17417007
DOI	10.1186/s12915-017-0404-4
Journal	BMC Biology
Issue Number	1
Volume Number	15
Language	English
Publisher	BioMed Central
Publisher Date	2017-07-24
Access Restriction	Open
Subject Keyword	Life Sciences Amino acid distribution Genome-wide statistical study Membrane protein Negative-not-inside/negative-outside rule Protein topology prediction Proteomics Transmembrane helix Transmembrane region prediction
Content Type	Text
Resource Type	Article
Subject	Ecology, Evolution, Behavior and Systematics Structural Biology Biochemistry, Genetics and Molecular Biology Plant Science Biotechnology Physiology Agricultural and Biological Sciences Cell Biology Developmental Biology
Journal Impact Factor	4.4/2023
5-Year Journal Impact Factor	5.4/2023

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

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

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