Coordinating the impact of structural genomics on the human α-helical transmembrane proteome

Abstract

With the recent successes in determining membrane protein structures, we explore the tractability of determining representatives for the entire human membrane proteome. This proteome contains 2,925 unique integral α-helical transmembrane domain sequences that cluster into 1,201 families sharing more than 25% sequence identity. Structures of 100 optimally selected targets would increase the fraction of modelable human α-helical transmembrane domains from 26% to 58%, thus providing structure/function information not otherwise available.

Figure 1. Flowchart of the analysis (Supplementary Notes 1 and 2)

In stage 1,α-helical transmembrane regions of all human sequences from the RefSeq-37 database34 were predicted by TMHMM2.0 and clustered with USEARCH at 98% sequence identity, resulting in 2,925 unique α-helical transmembrane domains with at least two predicted transmembrane helices. In stage 2, the current modeling coverage of these domains was assessed by automated comparative modeling using ModPipe. In stage 3, the 2,925 unique α-helical transmembrane domains were clustered at 25% sequence identity and 70% coverage thresholds using BLASTCLUST, resulting in 1,201 domain clusters. In stage 4, several target lists, including existing target lists of the nine PSI:Biology centers, were assessed by mapping the number and quality of models as a function of the number of targets; for example, if representative structures for the 100 largest clusters were determined, 1,400 additional α-helical transmembrane domains could be modeled based on at least 25% sequence identity to the closest known structure. In stage 5, the target sequence set was expanded by adding homologous sequences from other organisms extracted from UniProtKB.