Membrane proteins of the cytyplasmic membrane: Topology prediction:

A good introduction into membrane proteins and their structural organization can be found in the course "Principles of Protein Structure Using the Internet" at the Birkbeck University of London.

In contrast to outer membrane proteins whose membrane-embedded domain is formed by β sheets (Koebnik et al., 2000), the polypeptide chain of cytoplasmic membrane proteins traverses the membrane in the form of α helices.

The following websites allow to predict the membrane topology of cytyplasmic membrane proteins.

The lab of Gunnar von Heijne developed several algoriths to predict the topology of cytoplasmic membrane proteins and tested the corresponding rules experimentally. All algorithms are based on the observation that the amino acid compositions of the extra-membraneous loops differ significantly depending on whether they are located in the cytoplasm or outside of the cytoplasm. In particular, positively charges amino acids (arginine and lysine) act as discriminators, as expressed by the "positive-inside rule" (von Heijne and Gavel, 1988).

• TopPred 2
  Gunnar von Heijne (1992)
  Membrane protein structure prediction, hydrophobicity analysis and the positive-inside rule
  J. Mol. Biol. 225: 487-494

• TMpred
  K. Hofmann and W. Stoffel (1993)
  TMbase - A database of membrane spanning proteins segments
  Biol. Chem. Hoppe-Seyler 347: 166 ff

• SPLIT
• SPLIT 4.0
  D. Juretic, B. Lee, N. Trinajstic, and R.W. Williams (1993)
  Conformational preference functions for predicting helices in membrane proteins
  Biopolymers 33: 255-273

• MEMSAT
  D.T. Jones, W.R. Taylor, and J.M. Thornton (1994)
  A model recognition approach to the prediction of all-helical membrane protein structure and topology
  Biochemistry 33: 3038-3049

• TMAP, based on a single sequence
• TMAP, based on a multiple sequence alignment
  B. Persson and P. Argos (1994)
  Prediction of transmembrane segments in proteins utilising multiple sequence alignments
  J. Mol. Biol. 237 (2) 182-192
  and
  B. Persson and P. Argos (1996)
  Topology prediction of membrane proteins
  Protein Sci. 5 (2) 363-371

• TMHMM 1.0
  Erik L.L. Sonnhammer, Gunnar von Heijne, and Anders Krogh (1998)
  A hidden Markov model for predicting transmembrane helices in protein sequences
  In Proc. of Sixth Int. Conf. on Intelligent Systems for Molecular Biology, p 175-182 Ed J. Glasgow, T. Littlejohn, F. Major, R. Lathrop, D. Sankoff, and C. Sensen Menlo Park, CA: AAAI Press, 1998
  Introduction

• TMHMM 2.0
  Anders Krogh, B. Larsson, Gunnar von Heijne, and Erik L.L. Sonnhammer (2001)
  Predicting transmembrane protein topology with a hidden Markov model: application to complete genomes
  J. Mol. Biol. 305 (3) 567-580
  Introduction

• HMMTOP 1.1
  Gabor E. Tusnády and Istvan Simon (1998)
  Principles governing amino acid composition of integral membrane proteins: Applications to topology prediction
  J. Mol. Biol. 283: 489-506

• HMMTOP 2.0
  Gabor E. Tusnády and Istvan Simon (2001)
  The HMMTOP transmembrane topology prediction server
  Bioinformatics 17: 849-850

• PRED-TMR 1.0
  Claude Pasquier, V.J. Promponas, G.A. Palaios, J.S. Hamodrakas, and Stavros J. Hamodrakas (1999)
  A novel method for predicting transmembrane segments in proteins based on a statistical analysis of the SwissProt database: the PRED-TMR algorithm
  Protein Eng. 12: 381-385

• PRED-TMR 2.0
  Claude Pasquier and Stavros J. Hamodrakas (1999)
  An hierarchical artificial neural network system for the classification of transmembrane proteins
  Protein Eng. 12: 631-634

• OrienTM
  Theodore D. Liakopoulos, Claude Pasquier, and Stavros J. Hamodrakas (2001)
  A novel tool for the prediction of transmembrane protein topology based on a statistical analysis of the SwissProt database: the OrienTM algorithm
  Protein Eng. 14: 387-390

• TM Finder (Login)
  Charles M. Deber, Chen Wang, Li-Ping Liu, Andrew S. Prior, Shuchi Agrawal, Brenda L. Muskat, and A. Jamie Cuticchia (2001)
  TM Finder: a prediction program for transmembrane protein segments using a combination of hydrophobicity and nonpolar phase helicity scales
  Protein Sci. 10: 212-219

• MPEx
  Sajith Jayasinghe, Kalina Hristova, and Stephen H. White (2001)
  Energetics, stability, and prediction of transmembrane helices
  J. Mol. Biol. 312: 927-934
  -->

• TMHMMfix: Topology prediction with optional fixing and reliability score calculation
  Karin Melén, Anders Krogh, and Gunnar von Heijne (2003)
  Reliability measures for membrane protein topology prediction algorithms
  J. Mol. Biol. 327: 735-744

• Phobius
  Phobius
  Lukas Käll, Anders Krogh, and Erik L. Sonnhammer (2004)
  A combined transmembrane topology and signal peptide prediction method
  J. Mol. Biol. 338: 1027-1036

• PRODIV-TMHMM, PRO-TMHMM, and S-TMHMM
  Håkan Viklund and Arne Elofsson (2004)
  Best α-helical transmembrane protein topology predictions are achieved using hidden Markov models and evolutionary information
  Protein Sci. 13: 1908-1917

• PolyPhobius
  Lukas Käll, Anders Krogh, and Erik L. Sonnhammer (2005)
  An HMM posterior decoder for sequence feature prediction that includes homology information
  Bioinformatics 21: i251-i257

• PONGO
  Mauro Amico, Michele Finelli, Ivan Rossi, Andrea Zauli, Arne Elofsson, Håkan Viklund, Gunnar von Heijne, David Jones, Anders Krogh, Piero Fariselli, Pier Luigi Martelli, and Rita Casadio (2006)
  PONGO: a web server for multiple predictions of all-alpha transmembrane proteins
  Nucleic Acids Res. 34: W169-W272

• SCAMPI
  Andreas Bernsel, Håkan Viklund, Jenny Falk, Erik Lindahl, Gunnar von Heijne, and Arne Elofsson (2008)
  Prediction of membrane-protein topology from first principles
  Proc. Natl. Acad. Sci. USA 105: 7177-7181

• OCTOPUS
  Håkan Viklund and Arne Elofsson (2008)
  OCTOPUS: improving topology prediction by two-track ANN-based preference scores and an extended topological grammar
  Bioinformatics 24: 1662-1668

• SPOCTOPUS
  Håkan Viklund, Andreas Bernsel, M. Skwark, and Arne Elofsson (2008)
  SPOCTOPUS: a combined predictor of signal peptides and membrane protein topology
  Bioinformatics 24: 2928-2929

• TOPCONS
  Andreas Bernsel, Håkan Viklund, Aron Hennerdal, and Arne Elofsson (2009)
  TOPCONS: consensus prediction of membrane protein topology
  Nucleic Acids Res. 37: W465-W468

Comparison of algorithms to predict the membrane topology:
• Miklos Cserzo, Erik Wallin, Istvan Simon, Gunnar von Heijne, and Arne Elofsson (1997)
  Prediction of transmembrane alpha-helices in prokaryotic membrane proteins: the dense alignment surface method
  Protein Eng. 10: 673-676

• Johan Nilsson, Bengt Persson, and Gunnar von Heijne (2000)
  Consensus prediction of membrane protein topology
  FEBS Lett. 486: 267-269

• S. Möller, M.D. Croning, and R. Apweiler (2001)
  Evaluation of methods for the prediction of membrane spanning regions
  Bioinformatics 17: 646-653

• Gabor E. Tusnady and Istvan Simon (2001)
  Topology of membrane proteins
  J. Chem. Inf. Comput. Sci. 41: 364-368

• Chien Peter Chen and Burkhard Rost (2002)
  State-of-the-art in membrane protein prediction
  Applied Bioinformatics 1: 21-35

• Chien Peter Chen, Andrew Kernytsky, and Burkhard Rost (2002)
  Transmembrane helix predictions revisited
  Protein Science 11: 2774-2791

• Chien Peter Chen and Burkhard Rost (2002)
  Long membrane helices and short loops predicted less accurately
  Protein Science 11: 2766-2773

• Masami Ikeda, Masafumi Arai, Demelo M. Lao, and Toshio Shimizu (2002)
  Transmembrane topology prediction methods: a re-assessment and improvement by a consensus method using a dataset of experimentally-characterized transmembrane topologies
  In Silico Biol. 2: 19-33

• K. Melen, A. Krogh, and G. von Heijne (2003)
  Reliability measures for membrane protein topology prediction algorithms
  J. Mol. Biol. 327: 735-744

Statistics of transmembrane regions:
• Alessandro Senes, Mark Gerstein and Donald M. Engelman (2000)
  Statistical analysis of amino acid patterns in transmembrane helices: the GxxxG motif occurs frequently and in association with beta-branched residues at neighboring positions
  J. Mol. Biol. 296: 921-936

Cytoplasmic membrane proteins: Helix Packing:

The folding process of cytoplasmic membrane proteins can be described by the two-step model which was proposed by Popot and Engelman (Popot and Engelman, 1990): In the first step, membrane-spanning α helices are formed which then pack against each other within the plane of the membrane in the second step. This concept was extensively studied by experiments and simulations in the lab of Donald M. Engelman. As model peptides served the transmembrane helices of glycophorin A and of phospholamban. Similar studies were performed in the lab of Dieter Langosch. An overview about these studies can be found in:

• Gregg R. Dieckmann and William F. DeGrado (1997)
  Modeling transmembrane helical oligomers
  Curr. Opin. Structural. Biol. 7: 486-494

  Scientists from the Weizmann Institute in Israel wrote a program, kPROT (knowledged-based scale for the Propensity of Residue Orientation in Transmembrane segments), which based on statistical analyses predicts the orientation of transmembrane helices:

• Yitzhak Pilpel, Nir Ben-Tal, and Doron Lancet (1999)
  kPROT: a knowledge-based scale for the propensity of residue orientation in transmembrane segments. Application to membrane protein structure prediction
  J. Mol. Biol. 294: 921-935

  A more sophisticated programm is based on simulated annealing (no web version available):

• Rohit V. Pappu, Garland R. Marshall, and Jay W. Ponder (1999)
  A potential smoothing algorithm accurately predicts transmembrane helix packing
  Nat. Struct. Biol. 6: 50-55

Databases of membrane proteins:
• TMbase: Membrane protein database at the EMBnet (Switzerland)

• Collection of membrane proteins in a database at the University of Tokio (Japan) (OUTDATED)

• Collection of well-characterized membrane proteins (available via FTP)
  Steffen Möller, Evgenia V. Kriventseva, and Rolf Apweiler (2000)
  A collection of well characterised integral membrane proteins
  Bioinformatics 16: 1159-1160

• MPtopo database
  Sajith Jayasinghe, Kalina Hristova, and Stephen H. White (2001)
  MPtopo: A database of membrane protein topology
  Protein Sci. 10: 455-458

• DOLOP (Database Of bacterial LipOProteins)
  M. Madan Babu and K. Sankaran (2002)
  DOLOP—database of bacterial lipoproteins
  Bioinformatics 18: 641-643

• TMPDB database
  Masami Ikeda, Masafumi Arai, Toshikatsu Okuno, and Toshio Shimizu (2003)
  TMPDB: a database of experimentally-characterized transmembrane topologies
  Nucleic Acids Res. 31: 406-409

• PDB_TM database
  GáborTusnády, ZsuzsannaDosztányi, and István Simon (2004)
  Transmembrane proteins in the Protein Data Bank: identification and classification
  Bioinformatics 20: 406-409

Further web resources:
• RbDe: Residue-based Diagram editor - Online construction of topology models of alpha-helical transmembrane proteins
  K. Konvicka, F. Campagne, and H. Weinstein (2000)
  Interactive construction of residue-based diagrams of proteins: the RbDe web service
  Protein Eng. 13: 395-396

• CoPreTHi: Combined Prediction of Transmembrane Helices
  (1999)
  CoPreTHi: a Web tool which combines transmembrane protein segment prediction methods
  In Silico Biol. 1: 159-162

Sequence examples:

• Database of amino acid sequences via Entrez

• Bacteriorhodopsin from Halobacterium salinarium: Seven-helix bundle protein
• LacY: Lactose permease from Escherichia coli
• MalF: Subunit of the maltose permease from Escherichia coli
• MalG: Subunit of the maltose permease from Escherichia coli
• TonB from Escherichia coli: Protein with N-terminal transmembrane helix
• TolA from Escherichia coli: Protein with N-terminal transmembrane helix

• HrcT (HrpB8) from Xanthomonas campestris pv. vesicatoria
• HrcU (HrpC1) from Xanthomonas campestris pv. glycines
• HrcV (HrpC2) from Xanthomonas campestris pv. vesicatoria
• HrcQ (HrpD1) from Xanthomonas campestris pv. vesicatoria
• HrcR (HrpD2) from Xanthomonas campestris pv. vesicatoria
• HrcS (HrpD3) from Xanthomonas campestris pv. vesicatoria

Example of a multiple alignment:
• Multiple alignment of the N-terminal membrane anchors of TolA and TonB (Koebnik et al., 1993):

  IIISAVLHVILFAALIWSSFD   TolA (Escherichia coli) 
  LAFSVGIHGSVIAALLYVSGR   TonB (Yersinia enterocolitica)
  FVLSVGLHSALVAGLLYASVK   TonB (Serratia marcescens)
  TLLSVGIHGAVVAGLLYTSVH   TonB (Salmonella typhimurium)
  TLLSVCIHGAVVAGLLYTSVH   TonB (Escherichia coli)
  

• Example of a multiple sequence alignment in MSF format

Further references

Latest update: October 14, 2009

Ralf Koebnik
Institut de recherche pour le dèveloppement
UMR 5096, CNRS-UP-IRD
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Phone: +33 (0)4 67 41 62 28
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Email: koebnik(at)gmx.de
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