Transmembrane Domains

Abstract

Stretches of approximately 25 hydrophobic residues with an occasional polar residue of integral proteins that pass across membrane are known as transmembrane (TM) domains. Besides anchoring to the membrane they participate in the functions of these proteins in some unspecified way. A variety of membrane proteins with spans in the range 1–17 are present in human genome and those with 1, 4 and 7 spans are more common. Impacting a variety of cellular functions, these include receptors for growth factors, hormones and other ligands, two‐way membrane transporters, selective enzymes, channel proteins, energy‐transducing tiny molecular motor, molecular facilitators in signalling, adhesion, differentiation and proliferation. Highly variable sequences of these short stretches of hydrophobic residues of TM domains, with hardly any repetition, arise out of repeating XTX/XCX triplets in their complementary deoxyribonucleic acid (cDNA). They are encoded by a random exon make‐up, one exon coding for one or more domains and one domain coded by two exons with the junction between triplets and in some cases within a triplet.

Key Concepts:

  • Cell membrane is composed of hydrophobic phospholipid bilayer that separates two aqueous phases.

  • The selective permeability endows the membrane two‐way transport of desired materials.

  • Proteins attached to the membrane facilitate this exchange process.

  • Proteins that span across the bilayer in one or multiple passes are known as integral proteins or transmembrane (TM) proteins.

  • TM domains, composed of largely hydrophobic residues, anchor these proteins firmly to the membrane and also participate in the functions.

  • Topology of TM domains facilitates transfer of signals, channelling ions and transporting material.

  • The amino acid sequences of TM domains are highly variable and are not repeated.

  • Some of these short stretches of TM domains are encoded by two exons with junction between triplet or within triplet.

Keywords: transmembrane domains; membrane anchors; hydropathy; TMHMM; exon distribution; XTX/XCX‐enriched exons

Figure 1.

Arrangement of polypeptide chain in membrane spans. The membrane bilayer is represented as two lines with a middle broken line. The possible membrane passes are shown: (a) extended polypeptide chain, normally not found; (b) α‐helix shown as a box; (c) short helix, negative mismatch; (d) long helix, positive mismatch; (e) tilted helix; (f) bent helix; (g) half occupied sheet characteristic of channel proteins; and (h) β‐sheet shown as parallel arrows.

Figure 2.

Hydropathic plot of a protein to locate TM domains. The hatched peak corresponds to the hydrophobic residues given below, the purported membrane span of the insulin precursor protein: TMD, transmembrane domain; I: isoleucine; G: glycine; P: proline; L: leucine; F: phenylalanine; V: valine; S: serine; Y: tyrosine.

Figure 3.

Probability of occurrence of TM domains according to TMHMM plot. Amino acid sequence of 408 residues of β3 adrenergic receptor (Homo sapiens). The predicted seven helices (cyan blue) are shown in the sequence and with the residue numbers identified on the top of the figure, along with outside loop (red) and inside loop (purple). Adapted from Sonnhammer et al. .

Figure 4.

Distribution of the polypeptide chain in some typical monospanin proteins. The membrane span is shown as a box with the polypeptide chain extended into the extracellular and cytoplasmic sides. The number of residues of each domain is given: (a) α‐platelet‐derived growth factor receptor; (b) insulin receptor; (c) low‐density lipoprotein receptor; (d) polyIg receptor; (e) transferrin receptor; (f) membrane‐type frizzled‐related protein; (g) corin; and (h) CD4 protein.

Figure 5.

Architecture of the multimeric subunit c of F0adenosine triphosphatase (ATPase) and some dispanin proteins: (a) DEC/ENaC, a sodium channel; (b) UDPase, an ecto ATPase; (c) c subunit of F0ATPase (P1 form, Escherichia coli) (where the signal peptide is clipped shown by an arrow); the hatched helix forming the outer ring has the conserved residue E (glutamic acid); and (d) arrangement of the 10 subunits around the two helices of subunit γ of F0ATPase which is a part of the rotary unit, as viewed from one side of the membrane. The number of residues of each domain is given.

Figure 6.

Distribution of the polypeptides of tri‐, tetra‐ and penta‐spanin proteins: (a) leukotriene C4 synthase (long middle helix is shown tilted); (b) CD9 antigen; and (c) M83 protein. Hydrophilic residues occurring within the helices are shown by letter code (H: histidine; E: glutamic acid; N: asparagine; K: lysine; R: arginine). The number of residues of each domain is given.

Figure 7.

Distribution of the polypeptide chain of human β2 adrenergic G‐protein‐coupled receptor across the membrane: (a) distribution of the polypeptide in a clockwise connectivity of the seven helices with short loops, critical for activity; and (b) the crystal structure (Rasmussen et al., ) of the protein with the lines marking approximate membrane boundary (all the loops are not clear in the structure). Noradrenaline binds between helices III and V on the extracellular side, and the signal is transferred into the cytoplasm possibly through the TM and intracellular domains. The number of residues of each domain is given.

Figure 8.

Three‐dimensional structures of TM domains of selected membrane proteins. These were adapted from PDB files and the references from original publications are given in parenthesis. The lines are arbitrary membrane boundaries and the TM domains are shown in cyan blue. (a) Monoamine oxidase A of mitochondrial outer membrane (human), anchored by one TM domain (Son et al., ). (b) Structure of human estrone sulfatase, a dispanin with loop the two TM domains exposed at the boundary (Hernandez‐Guzman et al., ). (c) Open form of an E. coli mechanosensitive channel with three membrane spans (Wang et al., ). (d) Crystal structure of a tetraspanin protein involved in human cysteinyl leukotriene biosynthesis (Ago et al., ). (e) Structure of the KvAP voltage‐dependent K+ channel with six TM domains (Lee et al., ). (f) Crystal structure of bovine rhodopsin with seven TM domains (Stenkamp, ). (g) Structure of the lactose permease of E. coli, a multispanin (Abramson et al., ). (h) Cobalamin transporter with β‐barrel structure (Chimento et al., ).

close

References

Abramson J, Smirnova I, Kasho V et al. (2003) Structure and mechanism of the lactose permease of Escherichia coli. Science 301: 610–615.

Ago H, Kanaoka Y, Irikura D et al. (2007) Crystal structure of a human membrane protein involved in cysteinyl leukotriene biosynthesis. Nature 448: 609–612.

Boucheix C, Benoit P, Bachet P et al. (1991) Molecular cloning of CD9 antigen, a new superfamily of cell surface proteins. Journal of Biological Chemistry 266: 117–122.

Chimento DP, Mohanty AK, Kadner RJ and Wiener MC (2003) Substrate‐induced transmembrane signaling in the cobalamin transporter BtuB. Nature Structural Biology 10: 394–401.

Emorine LJ, Marullo S, Briend‐Sutren MM et al. (1989) Molecular characterization of the human beta 3‐adrenergic receptor. Science 245: 1118–1121.

Florian C and Schneider D (2010) Transmembrane helix‐helix interactions involved in ErbB receptor signaling. Cell Adhesion & Migration 4: 299–312.

Hernandez‐Guzman FG, Higashiyama T, Pangborn W, Osawa Y and Ghosh D (2003) Structure of human estrone sulfatase suggests functional roles of membrane association. Journal of Biological Chemistry 278: 22989–22997.

Krogh A, Larsson B, von Heijne G and Soonhammer ELL (2001) Predicting transmembrane protein topology with a hidden Markov model: application to complete genome. Journal of Molecular Biology 305: 567–580.

Kyte J and Doolittle RF (1982) A simple method for displaying the hydropathic character of a protein Journal of Molecular Biology 157: 105–132.

Langmann T, Porsch‐Orzcurumez M, Unkelbach U, Kulcken J and Schmitz G (2000) Genomic organization and characterization of the promoter of the human ATP‐binding cassette transporter‐G1 (ABCG1) gene. Biochimica et Biophysica Acta 1494: 175–180.

Lee SY, Lee A, Chen J and Mackinnon R (2005) Structure of the KvAP voltage‐dependent K+ channel and its dependence on the lipid membrane. Proceedings of the National Academy of Sciences of the USA 102(43): 15441–15446.

Moller S, Croning MDR and Apweiler R (2001) Evaluation of methods for the prediction of membrane spanning regions. Bioinformatics 17: 646–653.

Pan CJ, Lin B and Chou JY (1999) Transmembrane topology of human glucose 6‐phosphate transporter. Journal of Biological Chemistry 274: 13865–13869.

Raman P, Cherezova V and Caffrey M (2006) The membrane protein data bank. Cellular and Molecular Life Sciences 63: 36–51.

Ramasarma T (2000) In praise of the hydrogen bond. In: Lal M, Lillford PJ, Naik VM and Prakash V (eds) Supramolecular and Colloidal Structures in Biomaterials and Biosubstrates, pp. 450–462. London, UK: Imperial College Press of the Royal Society.

Rasmussen SG, Choi HJ, Rosenbaum DM et al. (2007) Crystal structure of the human B2adrenergic G‐protein‐coupled receptor. Nature 450: 383–388.

Son S‐E, Ma J, Kondou Y et al. (2008) Structure of human monoamine oxidase A at 2.2 Å resolution: the control of opening the entry for substrates/inhibitors. Proceedings of the National Academy of Sciences of the USA 105: 5739–5744.

Sonnhammer ELL, von Heijne G and Krogh A (1998) A hidden Markov model for predicting transmembrane helices in protein sequences. In: Glasgow J, Littlejohn T, Major F et al. (eds) Proceedings of the Sixth International Conference on Intelligent Systems for Molecular Biology, pp. 175–182. Menlo Park, CA: AAAI Press.

Stenkamp RE (2008) Alternative models for two crystal structures of bovine rhodopsin. Acta Crystallography Section D 64: 902–904.

Wang W, Black SS, Edwards MD et al. (2008) The structure of an open form of an E. coli mechanosensitive channel at 3.45 Å resolution. Science 321: 1179.

White SH and Wimley WC (1999) Membrane protein folding and stability: physical principles. Annual Review of Biophysics and Biomolecular Structure 28: 319–365.

Further Reading

Baldwin JM (1993) The probable arrangement of the helices in G protein‐coupled receptors. EMBO Journal 12: 1693–1703.

Benovic JL, Bovier M, Caron MG and Lefkowitz RL (1980) Regulation of adenyl cyclase‐coupled β‐adrenergic receptors. Annual Reviews of Cell Biology 4: 405–428.

Maecker HT, Todd SC and Levy S (1997) The tetraspanin superfamily: molecular facilitators. FASEB Journal 11: 428–442.

Ramasarma T (1996) Transmembrane domains participate in functions of integral membrane proteins. Indian Journal of Biochemistry and Biophysics 33: 20–29.

Sakharkar M, Long M, Tan TW and de Souza SJ (2000) Prediction tool for transmembrane segment in proteins. Nucleic Acids Research 28: 191–192. See also Web Links.

Savonov S, Daizadeh I, Fedorov A and Gilbert W (2000) The exon–intron database: an exhaustive database of protein‐coding intron‐containing genes. Nucleic Acids Research 28: 185–190. See also the Exon–Intron Database in Web Links.

Stock D, Leslie AGW and Walker JE (1999) Molecular architecture of the rotary motor in ATP synthase. Science 286: 1700–1705.

Yardley Y and Ulrich A (1998) Growth factor receptor tyrosine kinases. Annual Reviews of Biochemistry 57: 473–478.

Web Links

Genome Net. GenomeNet is a Japanese network of database and computational services for genome research and related research areas in molecular and cellular biology http://www.genome.ad.jp

http://blanco.biomol.uci.edu/Membrane_Proteins_xtal.html

Membrane Protein Data Bank (MPDB; http://www.lipidat.chemistry.ohio‐state.edu/MPDB/index.asp)

The Exon–Intron Database. An exhaustive database of protein‐coding intron‐containing genes http://golgi.harvard.edu/gilbert/eid/

TSEG, the prediction tool for Transmembrane SEGment in proteins http://www.genome.ad.jp/sit/tseg.html

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Ramasarma, T, Joshi, NV, Sekar, K, Uthayakumar, M, and Sherlin, D(Apr 2012) Transmembrane Domains. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0005051.pub2]