Signalling via Single‐Pass Transmembrane Proteins

Abstract

Single‐pass transmembrane proteins (TM1) are a diverse group of proteins characterised by a single transmembrane domain. In total, the authors found approximately 1300 TM1 proteins in the human genome, most of which have characterised functions. The extracellular domains of these proteins range up to 22 000 amino acids with an average size being six times larger than intracellular domains. This suggests that these proteins have evolved the capacity to bind a wide array of ligands and substrates. Consequently, these proteins are involved in many processes, such as adhesion, migration, growth and cell death, among others. Although many act as receptors for first messengers (extracellular signalling molecules), they can also serve as ligands, adaptors, proteases and coreceptors. Herein, the authors provide a broad overview of these different roles along with examples of their involvement in pathological and physiological situations.

Key Concepts:

  • Single‐pass transmembrane proteins participate in signalling in a variety of ways, either as ligands, receptors, enzymes coreceptors and/or adaptors.

  • TM1 proteins appear to have undergone evolutionary expansion as a function of body plan complexity.

  • The extracellular domains of TM1 proteins cluster well based on family, whereas the intracellular domains do not.

  • TM1 proteins are adapted to bind very large substrates/ligands compared with other receptor families (ion channels and GPCRs).

  • TM1 have roles in every organ system and are particularly important in the immune and nervous systems.

Keywords: signal transduction; single‐pass transmembrane proteins; receptor tyrosine kinase; type‐1 single pass transmembrane protein; proteases; axon guidance; immune signalling; cell adhesion

Figure 1.

Similarity trees, built using extracellular (a) and intracellular (b) TM1 domain analysis. The amino acid sequences of the 1281 human TM1 were extracted from protein database Uniprot (http://www.uniprot.org/); extracellular and intracellular regions were separated by identifying the transmembrane region using TMHMM web service (http://www.cbs.dtu.dk/services/TMHMM/). Pairwise alignment was performed using the program MEGA (version 5.1) and the ClustalW algorithm against the BLOSUM matrix. The tree represents the most parsimonious explanation for the differences in the alignment of the extracellular domains or intracellular domains. Identified clusters of receptors are coloured depending on their function: Receptors with enzymatic activity (red), ligands to specific receptors (green), receptors involved in cell adhesion and axon guidance (blue), receptors involved in immune function (pink) and uncategorised receptors (purple). Numeric differences in the clusterisation of receptor families are presented in Table . High‐resolution images of these trees are available at http://www.deppmannlab.com/TM1.

Figure 2.

The histograms showing the distribution of amino acid length of the intracellular (orange) and extracellular (blue) domains used to generate the similarity tree. The intracellular domains have a median of 56 amino acids and a mean of 105.6 amino acids. The median and mean length of the extracellular domains is 380 and 557.9 amino acids, respectively. Blue represents the extracellular domain sequences and orange represents the intracellular domain sequences. The extracellular domain histogram was truncated for readability. One protein (mucin 16) was not shown with an extracellular domain of 22 100 amino acids.

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Pahl, Matthew C, Askinazi, Olga L, Hamilton, Catherine, Cheng, Irene, Cichewicz, Karol, Kuhn, Jason, Manohar, Sumanth, and Deppmann, Christopher D(Oct 2013) Signalling via Single‐Pass Transmembrane Proteins. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0025160]