Abstract
Transmembrane proteins are involved in many essential cell processes such as signal transduction, transport, and protein trafficking, and hence many are implicated in different disease pathways. Further, as the structure and function of proteins are correlated, investigating a group of proteins with the same tertiary structure, i.e., the same number of transmembrane regions, may give understanding about their functional roles and potential as therapeutic targets. This analysis investigates the previously unstudied group of proteins with five transmembrane-spanning regions (5TM). More than half of the 58 proteins identified with the 5TM architecture belong to 12 families with two or more members. Interestingly, more than half the proteins in the dataset function in localization activities through movement or tethering of cell components and more than one-third are involved in transport activities, particularly in the mitochondria. Surprisingly, no receptor activity was identified within this dataset in large contrast with other TM groups. The three major 5TM families, which comprise nearly 30% of the dataset, include the tweety family, the sideroflexin family and the Yip1 domain (YIPF) family. We also analyzed the evolutionary origin of these three families. The YIPF family appears to be the most ancient with presence in bacteria and archaea, while the tweety and sideroflexin families are first found in eukaryotes. We found no evidence of common decent for these three families. About 30% of the 5TM proteins have prominent expression in the brain, liver, or testis. Importantly, 60% of these proteins are identified as cancer prognostic markers, where they are associated with clinical outcomes of various tumor types. Nearly 10% of the 5TMs are still not fully characterized and further investigation of their functional activities and expression is warranted. This study provides the first comprehensive analysis of proteins with the 5TM architecture, providing details of their unique characteristics.
Highlights
25–30% of the ∼20,000 protein coding genes in Homo sapiens code for alpha-helical transmembrane proteins (Almén et al, 2009; Fagerberg et al, 2010; Attwood et al, 2017)
The other two families and 14 singlets contain Pfam domains or belong to protein families that contain additional members that do not have five membrane regions predicted. The majority of this compact dataset is comprised of complete small families and unique single proteins that contain five membrane-spanning regions, as opposed to say the 7 TM architecture that is primarily comprised of the large homologous G protein-coupled receptors (GPCR) superfamily with 800+ proteins
Functional annotations and localization information were compiled through Gene Ontology (GO) descriptions (Binns et al, 2009; The Gene Ontology Consortium., 2019), the Human Protein Atlas (Thul et al, 2017), and the PANTHER classification database (Mi et al, 2019)
Summary
25–30% of the ∼20,000 protein coding genes in Homo sapiens code for alpha-helical transmembrane proteins (Almén et al, 2009; Fagerberg et al, 2010; Attwood et al, 2017). Transmembrane (TM) proteins are involved in many crucial cell processes including receptor and signaling transduction pathways, transport of ions and molecules across impermeable membranes, protein targeting and intracellular transport, as well as membrane trafficking (Müller et al, 2008). Subcellular compartments within cells are maintained by membranes and organelle-specific activities are based on the distribution and function of different transmembrane proteins. The development of organelles has been aided by the evolutionary retargeting of membrane proteins to shared or different subcellular compartments, and the ultimate protein destinations can vary depending on physiological conditions, cell types, developmental expression, and lineages (Gabaldón and Pittis, 2015). Investigating the topology, localization, and expression of homologous protein families can provide insight in their different functional activities and identify potential candidates for further studies on drug targets
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