Abstract
BackgroundMembrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins.ResultsHere we mined the human proteome and identified the membrane proteome subset using three prediction tools for alpha-helices: Phobius, TMHMM, and SOSUI. This dataset was reduced to a non-redundant set by aligning it to the human genome and then clustered with our own interactive implementation of the ISODATA algorithm. The genes were classified and each protein group was manually curated, virtually evaluating each sequence of the clusters, applying systematic comparisons with a range of databases and other resources. We identified 6,718 human membrane proteins and classified the majority of them into 234 families of which 151 belong to the three major functional groups: receptors (63 groups, 1,352 members), transporters (89 groups, 817 members) or enzymes (7 groups, 533 members). Also, 74 miscellaneous groups with 697 members were determined. Interestingly, we find that 41% of the membrane proteins are singlets with no apparent affiliation or identity to any human protein family. Our results identify major differences between the human membrane proteome and the ones in unicellular organisms and we also show a strong bias towards certain membrane topologies for different functional classes: 77% of all transporters have more than six helices while 60% of proteins with an enzymatic function and 88% receptors, that are not GPCRs, have only one single membrane spanning α-helix. Further, we have identified and characterized new gene families and novel members of existing families.ConclusionHere we present the most detailed roadmap of gene numbers and families to our knowledge, which is an important step towards an overall classification of the entire human proteome. We estimate that 27% of the total human proteome are alpha-helical transmembrane proteins and provide an extended classification together with in-depth investigations of the membrane proteome's functional, structural, and evolutionary features.
Highlights
Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins
One of the most referenced papers regarding the percentage of membrane proteins in proteomes is from 2001 where the membrane topology prediction method TMHMM was applied on a number of proteomes from different species to estimate the membrane protein content, for example, Caenorhabditis elegans (31%), Escherichia coli (21%) and Drosophila melanogaster (20%) [2]
We created a dataset of 13,208 human membrane proteins based on consensus predictions of α-helices with three applications, Phobius [12], TMHMM [2], and SOSUI [13], in all 69,731 sequences in the human proteome dataset provided by International Protein Index (IPI) (v3.39)
Summary
Membrane proteins form key nodes in mediating the cell's interaction with the surroundings, which is one of the main reasons why the majority of drug targets are membrane proteins. Integral membrane proteins play a key role in detecting and conveying outside signals into cells, allowing them to interact and respond to their environment in a specific manner. They form principal nodes in hormonal and neuronal signaling and attract large interest in therapeutic interventions as the majority of drug targets are associated to the cell's membrane. Four commonly used membrane topology prediction methods were applied to the human proteome [4]. Based on the range of predictions by the different methods 15 to 39% of the human proteome was dedicated to be membrane proteins, clearly illustrating how difficult it is to estimate the number with automatic approaches. While several individual protein and gene families have been relatively well described, for example, the GPCRs [9] and Voltage-gated ion channels [10], there is a considerable number of genes that have remained unexplored
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