Transmembrane Domains

T Ramasarma, Indian Institute of Science, Bangalore, India
NV Joshi, Indian Institute of Science, Bangalore, India
K Sekar, Indian Institute of Science, Bangalore, India
M Uthayakumar, Indian Institute of Science, Bangalore, India
D Sherlin, Indian Institute of Science, Bangalore, India

Published online: April 2012

DOI: 10.1002/9780470015902.a0005051.pub2

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. (1998).
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 F0 adenosine triphosphatase (ATPase) and some dispanin proteins: (a) DEC/ENaC, a sodium channel; (b) UDPase, an ecto ATPase; (c) c subunit of F0 ATPase (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 F0 ATPase 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., 2007) 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., 2008). (b) Structure of human estrone sulfatase, a dispanin with loop the two TM domains exposed at the boundary (Hernandez‐Guzman et al., 2003). (c) Open form of an E. coli mechanosensitive channel with three membrane spans (Wang et al., 2008). (d) Crystal structure of a tetraspanin protein involved in human cysteinyl leukotriene biosynthesis (Ago et al., 2007). (e) Structure of the KvAP voltage‐dependent K+ channel with six TM domains (Lee et al., 2005). (f) Crystal structure of bovine rhodopsin with seven TM domains (Stenkamp, 2008). (g) Structure of the lactose permease of E. coli, a multispanin (Abramson et al., 2003). (h) Cobalamin transporter with β‐barrel structure (Chimento et al., 2003).
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 References
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    book 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.
    book 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.
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    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.
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 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
    ePath 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
    ePath http://blanco.biomol.uci.edu/Membrane_Proteins_xtal.html
    ePath Membrane Protein Data Bank (MPDB; http://www.lipidat.chemistry.ohio‐state.edu/MPDB/index.asp)
    ePath The Exon–Intron Database. An exhaustive database of protein‐coding intron‐containing genes http://golgi.harvard.edu/gilbert/eid/
    ePath TSEG, the prediction tool for Transmembrane SEGment in proteins http://www.genome.ad.jp/sit/tseg.html

Related Sub-Topics:

Membrane Proteins | Protein Structure | Proteins: Structure, Function, Metabolism
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Article Title: Transmembrane Domains
 
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]