Technical Highlight - August 2013
Short description: All PSI Membrane Protein Structure Centers and one large-scale production center have joined forces to create a strategy to maximize our understanding of the human transmembrane proteome.
Membrane proteins with α-helical transmembrane domains are among the most abundant and diverse protein classes, comprising a predicted 25% of the human proteome. They also play important biological roles and are the target of many drugs. However, membrane proteins pose technical challenges in their purification and structural analysis. They are vastly underrepresented among the approximately 85,000 entries in the PDB, accounting for only 1,035 entries, of which 408 are unique currently.
Recent advances in membrane protein structure determination have prompted the nine PSI:Biology centers and one large-scale production center to coordinate their efforts in filling this gap. By optimizing target selection for structural determination, Sali, Stevens, Stroud and colleagues (PSI CSMP, GPCR, MPID, MPSBC, MPSbyNMR, NYCOMPS, NYSGRC, TEMIMPS, TMPC, TransportPDB) estimate that useful homology models could be generated for more than half of the human transmembrane proteome, from only an additional 100 structures. They describe a strategy to identify the 100 α-helical transmembrane proteins whose structural determination would make the greatest contribution to current structural modeling efforts.
While the authors initially used established methods to identify α-helical transmembrane domains, two additional parameters were employed to guide target selection. First, α-helical transmembrane sequences must share more than 25% sequence identity to facilitate comparative structure modeling. Second, by prioritizing the investigation of the largest domain families with no known structures, the authors maximized the total coverage provided by a limited number of new protein structures. They predict that structural determination of the 100 proteins selected by this approach will increase the coverage of the human α-helical transmembrane proteome from 26 to 58%.
By providing a framework to coordinate large-scale structural genomic analyses among multiple PSI centers, the authors have defined an optimal path in a technically challenging field. Moreover, two-thirds of the 100 target proteins identified are on the target lists of individual PSI centers at present. The work also concludes that the yield of structural information can be improved by including homologs from other organisms. This comprehensive analysis will ultimately reveal the structural basis of the essential cellular functions of transmembrane proteins.
U. Pieper et al. Coordinating the impact of structural genomics on the human α-helical transmembrane proteome.
Nat Struct Mol Biol. 20, 135-138 (2013). doi:10.1038/nsmb.2508