Introduction to the Virtual Issue: Learning about Proteins that Live in Membranes

James U. Bowie

The papers in this virtual issue were selected to emphasize the different areas that Protein Science has happily accommodated. It is not meant to be an exhaustive list of all the work that has been reported here. Indeed, for every paper selected there are many others that could have been chosen

Protein Science has seen its share of new structures, a few of which were culled for this virtual issue. These include one of the earliest porin structures, which appeared when there were only a handful of structures known¹, an interesting structure of a porin caught in the act of transporting a Trojan horse antibiotic², and a structure of the cytoplasmic domain of a metal transporter published this fall³. While crystallography has been the primary method for membrane protein structure determination, both solution and solid state NMR have been contributors as well. One of the selected papers from Marassi and Opella describe further improvements in the promising method of solid state NMR⁴.

A group of highlighted papers characterizes the number, diversity and characteristics of membrane proteins. Several of the papers provided some of the earliest estimates of the number helical and beta barrel membrane proteins^5,6. Another paper suggests that the number of membrane protein folds is small enough that we can hope to have a representative set of structures in the foreseeable future⁷. How fast this happens depends on the rate of structure determination and a 2004 paper by Stephen White provides an estimate by extrapolating the exponential growth seen at the time⁸. According to the prediction, we should have ~300 structures by now, but the number is unfortunately closer to 200. The increase is still exponential, but the exponent is apparently smaller that it appeared earlier.

Structural biologists clearly need to pick up the pace and other papers in this virtual issue provide help in this regard. Iwata’s group collected recent data from membrane protein crystallization efforts and developed a new sparse matrix crystallization screen⁹. Gellman’s group presented one of the first novel detergents for membrane protein solubilization and crystallization, an area that continues to develop¹⁰. An interesting method for stabilizing membrane proteins by introducing a metal binding site was recently described by Baneres and co-workers¹¹. Nanodisks are an exciting technology for many aspects of membrane protein work and the first incorporation of a membrane protein into a nanodisk was reported in a paper included this virtual issue¹².

One of the major barriers to the study of membrane proteins is simply the problem of producing them. Protein Science has been a major venue for expression and production methods, which is illustrated by a few selected papers. One paper in this virtual issue describes a successful fusion approach for G-protein coupled receptor expression¹³. In addition, new screens and selections for E. coli mutants that improve expression are highlighted^14,15

Protein Science has traditionally been a forum for developments in structure prediction and folding. Among the many efforts to predict membrane protein topology described in the journal, two of the more recent papers were selected^16,17. One of them describes the nice idea of using experimental constraints to improve topology prediction. A paper from Bill DeGrado’s group describing a method for measuring stabilities is highlighted¹⁸. Several selected reviews on protein folding will point to additional articles in the journal^19,20.

As this virtual issue illustrates, Protein Science has been an ideal place to report membrane protein research. The journal looks forward to publishing many more exciting stories in the future.

1. Kreusch A, Neubuser A, Schiltz E, Weckesser J, Schulz GE (1994) Structure of the membrane channel porin from Rhodopseudomonas blastica at 2.0 A resolution. Protein Sci 3:58.

2. Ferguson AD, Braun V, Fiedler HP, Coulton JW, Diederichs K, Welte W (2000) Crystal structure of the antibiotic albomycin in complex with the outer membrane transporter FhuA. Protein Sci 9:956.

3. Tan K, Sather A, Robertson JL, Moy S, Roux B, Joachimiak A (2009) Structure and electrostatic property of cytoplasmic domain of ZntB transporter. Protein Sci 18:2043.

4. Marassi FM, Opella SJ (2003) Simultaneous assignment and structure determination of a membrane protein from NMR orientational restraints. Protein Sci 12:403.

5. Wallin E, von Heijne G (1998) Genome-wide analysis of integral membrane proteins from eubacterial, archaean, and eukaryotic organisms. Protein Sci 7:1029.

6. Wimley WC (2002) Toward genomic identification of beta-barrel membrane proteins: composition and architecture of known structures. Protein Sci 11:301.

7. Oberai A, Ihm Y, Kim S, Bowie JU (2006) A limited universe of membrane protein families and folds. Protein Sci 15:1723.

8. White SH (2004) The progress of membrane protein structure determination. Protein Sci 13:1948.

9. Newstead S, Ferrandon S, Iwata S (2008) Rationalizing alpha-helical membrane protein crystallization. Protein Sci 17:466.

10. Yu SM, McQuade DT, Quinn MA, Hackenberger CP, Krebs MP, Polans AS, Gellman SH (2000) An improved tripod amphiphile for membrane protein solubilization. Protein Sci 9:2518.

11. Martin A, Damian M, Laguerre M, Parello J, Pucci B, Serre L, Mary S, Marie J, Baneres JL (2009) Engineering a G protein-coupled receptor for structural studies: stabilization of the BLT1 receptor ground state. Protein Sci 18:727.

12. Bayburt TH, Sligar SG (2003) Self-assembly of single integral membrane proteins into soluble nanoscale phospholipid bilayers. Protein Sci 12:2476.

13. Yeliseev AA, Wong KK, Soubias O, Gawrisch K (2005) Expression of human peripheral cannabinoid receptor for structural studies. Protein Sci 14:2638.

14. Link AJ, Skretas G, Strauch EM, Chari NS, Georgiou G (2008) Efficient production of membrane-integrated and detergent-soluble G protein-coupled receptors in Escherichia coli. Protein Sci 17:1857.

15. Massey-Gendel E, Zhao A, Boulting G, Kim HY, Balamotis MA, Seligman LM, Nakamoto RK, Bowie JU (2009) Genetic selection system for improving recombinant membrane protein expression in E. coli. Protein Sci 18:372.

16. Rapp M, Drew D, Daley DO, Nilsson J, Carvalho T, Melen K, De Gier JW, Von Heijne G (2004) Experimentally based topology models for E. coli inner membrane proteins. Protein Sci 13:937.

17. Viklund H, Elofsson A (2004) Best alpha-helical transmembrane protein topology predictions are achieved using hidden Markov models and evolutionary information. Protein Sci 13:1908.

18. Cristian L, Lear JD, DeGrado WF (2003) Determination of membrane protein stability via thermodynamic coupling of folding to thiol-disulfide interchange. Protein Sci 12:1732.

19. DeGrado WF, Gratkowski H, Lear JD (2003) How do helix-helix interactions help determine the folds of membrane proteins? Perspectives from the study of homo-oligomeric helical bundles. Protein Sci 12:647.

20. Langosch D, Arkin IT (2009) Interaction and conformational dynamics of membrane-spanning protein helices. Protein Sci 18:1343.