From Protein Structure to Function with Bioinformatics.pdf

Chapter 4Membrane Protein Structure PredictionTimothy Nugent and David T. JonesAbstract Transmembrane (TM) proteins fulfil many crucial cellular functionsand make up a large fraction of any given proteome with estimates suggesting upto 30% of all human genes may encode alpha-helical TM proteins. However, relativelyfew high resolution TM protein structures are known, making it all the moreimportant to extract as much structural information as possible from amino acidsequences. In this chapter, we discuss current topology and structure predictionmethods against a background of knowledge that has been gleaned from membraneprotein sequence and structures analysis. We attempt to highlight potential pitfallsand identify major issues yet to be resolved.4.1 IntroductionTransmembrane (TM) proteins are involved in a wide range of important biologicalprocesses such as cell signalling, transport of membrane-impermeable molecules,cell-cell communication, cell recognition and cell adhesion. Many are also primedrug targets, and it has been estimated that more than half of all drugs currently onthe market target membrane proteins (Klabunde and Hessler 2002). However, dueto the experimental difficulties involved in obtaining high quality crystals, this classof protein is severely under-represented in structural databases, making up only 1%of known structures in the PDB (White 2004). Given the biological and pharmacologicalimportance of TM proteins, an understanding of their structure and topology– the total number of TM helices, their boundaries and in/out orientation relative tothe membrane – is essential for functional analysis and directing further experimentalwork. In the absence of structural data, bioinformatic strategies thus turn tosequence-based prediction methods.T. Nugent and D.T. Jones*Bioinformatics Group, Department of Computer Science, University College, London, WC1E 6BT, UK*Corresponding author: e-mail: d.jones@cs.ucl.ac.ukD.J. Rigden (ed.) From Protein Structure to Function with Bioinformatics, 91© Springer Science + Business Media B.V. 2009