Membrane-spanning α-helical barrels as tractable protein-design targets

Ai Niitsu, Jack W. Heal, Kerstin Fauland, Andrew R. Thomson, Derek N. Woolfson*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)peer-review

9 Citations (Scopus)
247 Downloads (Pure)

Abstract

The rational (de novo) design of membrane-spanning proteins lags behind that for water-soluble globular proteins. This is due to gaps in our knowledge of membrane-protein structure, and experimental difficulties in studying such proteins compared to water-soluble counterparts. One limiting factor is the small number of experimentally determined threedimensional structures for transmembrane proteins. By contrast, many tens of thousands of globular protein structures provide a rich source of ‘scaffolds’ for protein design, and the means to garner sequence-to-structure relationships to guide the design process. The a-helical coiled coil is a protein-structure element found in both globular and membrane proteins, where it cements a variety of helix-helix interactions and helical bundles. Our deep understanding of coiled coils has enabled a large number of successful de novo designs. For one class, the a-helical barrels-that is, symmetric bundles of five or more helices with central accessible channels-there are both water-soluble and membrane-spanning examples. Recent computational designs of water-soluble a-helical barrels with five to seven helices have advanced the design field considerably. Here we identify and classify analogous and more complicated membrane-spanning a-helical barrels from the Protein Data Bank. These provide tantalizing but tractable targets for protein engineering and de novo protein design. This article is part of the themed issue ‘Membrane pores: from structure and assembly, to medicine and technology’.

Original languageEnglish
Article number20160213
Number of pages6
JournalPhilosophical Transactions B: Biological Sciences
Volume372
Issue number1726
Early online date19 Jun 2017
DOIs
Publication statusPublished - 5 Aug 2017

Structured keywords

  • BrisSynBio
  • Bristol BioDesign Institute

Keywords

  • helical barrel
  • coiled coil
  • de novo protein design
  • transmembrane proteins
  • SYNTHETIC BIOLOGY

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