Functional characterization of 3D protein structures informed by human genetic diversity

Abstract

Sequence variation data of the human proteome can be used to analyze 3D protein structures to derive functional insights. We used genetic variant data from nearly 140,000 individuals to analyze 3D positional conservation in 4,715 proteins and 3,951 homology models using 860,292 missense and 465,886 synonymous variants. Sixty percent of protein structures harbor at least one intolerant 3D site as defined by significant depletion of observed over expected missense variation. Structural intolerance data correlated with deep mutational scanning functional readouts for PPARG, MAPK1/ERK2, UBE2I, SUMO1, PTEN, CALM1, CALM2, and TPK1 and with shallow mutagenesis data for 1,026 proteins. The 3D structural intolerance analysis revealed different features for ligand binding pockets and orthosteric and allosteric sites. Large-scale data on human genetic variation support a definition of functional 3D sites proteome-wide.

Comprehensive characterization of amino acid positions in protein structures reveals molecular effect of missense variants

“…These general characteristics of 3D hotspots that we (Fig. 2) and others (20)(21)(22)64) have identified are necessary for making an educated guess about the effect of missense variations in any protein without knowing their function. But the insights gathered from these results are inherently limited because of the sheer diversity of proteins' structural and functional properties.…”

Gastrointestinal (GI) Tract Microbiome-Derived Neurotoxins—Potent Neuro-Inflammatory Signals From the GI Tract via the Systemic Circulation Into the Brain

“…In the most recent estimate analyses of the GI-tract metagenomes of ∼2100 donors well over 22.3 million nonredundant prokaryotic genes were detected, and at least half of all the genes identified were unique to an individual (Tierney et al, 2019). When compared to the established human genome content of 26.6 thousand protein-encoding transcripts of the human genome sequencing project obtained about ∼18 years ago (Fields et al, 1994;Venter et al, 2001;Hicks et al, 2019) the number of microbial genes in the human GI-tract microbiome alone outnumbers human genes by about 837 to 1 (Tierney et al, 2019). Another interesting fact is that of the 52 major divisions of bacteria identified to date, only 2 phyla are known to predominate in the human GI-tract microbiomethe Gram-negative Bacteroidetes (representing about ∼20-30% of all GI-tract resident bacteria) and the Gram-positive Firmicutes (representing ∼70-80% of the total) with relatively minor contributions by Actinobacteria (∼3%), Proteobacteria (∼1%), Fusobacteria (∼0.1%) and Verrucomicrobia (0.1%).…”

Advances in Genomics for Drug Development

“…Population genomic data can also be used to characterize prioritization of drug target sites in the context of protein structures [ 119 ]. We have previously analyzed the 3D intolerance to mutation of 97 proteins that included known drug targets with a bound ligand and proteins with known allosteric sites [ 120 ]. Active sites were most constrained, followed by allosteric, protein–protein interaction, and ligand-binding pockets.…”

“…For example, antineoplastic and immunomodulating agents preferentially target mutation-intolerant sites. We speculated that the identification of mutation-intolerant 3D sites and domains in drug targets could be exploited for rational drug design and for analysis of drug screening results [ 120 ].…”