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.

Less is More: Membrane Protein Digestion Beyond Urea–Trypsin Solution for Next-level Proteomics

“…Nearly 25% of 29,375 unique protein sequences in human proteome contain one or more TM helices (3). Prominently, TM neurotransmitter receptors such as G protein-coupled receptors (GPCR) and ligand-gated ion channels (LGIC)-with most members yet to tap-exceed 50% of current therapeutic targets (3).…”

“…Nearly 25% of 29,375 unique protein sequences in human proteome contain one or more TM helices (3). Prominently, TM neurotransmitter receptors such as G protein-coupled receptors (GPCR) and ligand-gated ion channels (LGIC)-with most members yet to tap-exceed 50% of current therapeutic targets (3). However, hydrophobic and prone to aggregation, membrane proteins have long vexed bottom-up proteomics with under-representation in every metric, including: sequence coverage, peptide spectrum matches (PSMs), unique peptides, and peptide reproducibility (2, 4, 5)-regardless of global lysates or highly purified samples-contrasting facile soluble proteins.…”

“…Abundant in human genome and pivotal in cell signaling, transmembrane (TM) proteins are coveted therapeutic targets (3), yet tremendously difficult to study at all levels (1)-including proteomics (2,4,5). Nearly 25% of 29,375 unique protein sequences in human proteome contain one or more TM helices (3).…”

Structure Prediction of Transmembrane Proteins

“…Known TMP structures by now make possible to create model for 26 % of the human α-helical transmembrane proteome using homology modeling (see Sect. 9.4.2.1), this ratio could be increased up to 56 % with 100 more new evenly selected and determined structures [115].…”

Lipidic Cubic Phase Technologies for Structural Studies of Membrane Proteins

“…They constitute about 30 % of the proteome in most organisms (Fagerberg et al 2010) and play crucial roles in many cellular and physiological processes. Due to their involvement in a large number of human pathological conditions, MPs serve as important therapeutic targets; more than 60 % of drugs currently in the market bind to and modulate MP function (Pieper et al 2013). MPs provide links between the extracellular and the intracellular environments and include receptors that are central to signal transduction, transporters, ion channels, enzymes, and others, such as adhesion proteins involved in cell-cell recognition.…”