Abstract
The assembly of proteins into complexes and their interactions with other biomolecules are often vital for their biological function. While it is known that mutations at protein interfaces have a high potential to be damaging and cause human genetic disease, there has been relatively little consideration for how this varies between different types of interfaces. Here we investigate the properties of human pathogenic and putatively benign missense variants at homomeric (isologous and heterologous), heteromeric, DNA, RNA and other ligand interfaces, and at different regions in proteins with respect to those interfaces. We find that different types of interfaces vary greatly in their propensity to be associated with pathogenic mutations, with homomeric heterologous and DNA interfaces being particularly enriched in disease. We also find that residues that do not directly participate in an interface, but are close in three-dimensional space, show a significant disease enrichment. Finally, we observe that mutations at different types of interfaces tend to have distinct property changes when undergoing amino acid substitutions associated with disease, and that this is linked to substantial variability in their identification by computational variant effect predictors.
Highlights
Single nucleotide variants (SNVs) are the most common type of human genetic variation [1]
We investigate the enrichment of pathogenic mutations within different regions of proteins and different types of interfaces
We considered only variants that could be mapped to residues in published Protein Data Bank (PDB) structures; this resulted in a total of 495,076 putatively benign missense variants in 4033 genes, and 19,175 pathogenic missense variants in 1754 genes
Summary
Single nucleotide variants (SNVs) are the most common type of human genetic variation [1]. While many SNVs in protein-coding regions of the genome are associated with human disease, the vast majority have no noticeable clinical impact [2]. Distinguishing novel disease-causing SNVs from those that are benign is a major ongoing challenge for the field of bioinformatics. Protein misfolding and destabilisation have long been held as primary mechanisms by which mutations cause disease [3], and it is well established that pathogenic missense mutations are enriched within interior residues of proteins relative to the surface [4,5,6]. There has been increasing recognition of the importance of protein interfaces as hubs for disease-associated mutants [7,8,9]. Experimental work strongly supports the idea that many pathogenic alleles do not destabilise protein folding but instead perturb protein interactions [12]
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