Solvent Accessibility of Residues Undergoing Pathogenic Variations in Humans: From Protein Structures to Protein Sequences

Abstract

Solvent accessibility (SASA) is a key feature of proteins for determining their folding and stability. SASA is computed from protein structures with different algorithms, and from protein sequences with machine-learning based approaches trained on solved structures. Here we ask the question as to which extent solvent exposure of residues can be associated to the pathogenicity of the variation. By this, SASA of the wild-type residue acquires a role in the context of functional annotation of protein single-residue variations (SRVs). By mapping variations on a curated database of human protein structures, we found that residues targeted by disease related SRVs are less accessible to solvent than residues involved in polymorphisms. The disease association is not evenly distributed among the different residue types: SRVs targeting glycine, tryptophan, tyrosine, and cysteine are more frequently disease associated than others. For all residues, the proportion of disease related SRVs largely increases when the wild-type residue is buried and decreases when it is exposed. The extent of the increase depends on the residue type. With the aid of an in house developed predictor, based on a deep learning procedure and performing at the state-of-the-art, we are able to confirm the above tendency by analyzing a large data set of residues subjected to variations and occurring in some 12,494 human protein sequences still lacking three-dimensional structure (derived from HUMSAVAR). Our data support the notion that surface accessible area is a distinguished property of residues that undergo variation and that pathogenicity is more frequently associated to the buried property than to the exposed one.

Analysis and Interpretation of the Impact of Missense Variants in Cancer

“…In particular, Figure 6b shows that the majority of PCVs (~58%) are occurring in buried regions (RSA ≤ 0.2), while~75% of putative benign variants are in exposed regions (RSA > 0.2). The fraction of PCVs in exposed regions, which we found in our dataset, is higher than the value reported for pathogenic variants [63], nevertheless, due to the reduced size of our dataset, such a difference is not statistically significant.…”

“…The analysis of the mutation sites in all the protein structures examined indicates that ~30% of them are buried from the solvent. Generally, the consequence of a mutation in the protein core are more likely to be deleterious, leading to protein misfolding [ 63 ]. If the mutated residue is on the surface of the protein, a minimal rearrangement of the exposed region may occur, however the global folding of the protein variant is maintained as well as its expression in the cell [ 64 , 65 ].…”

Missense Variation in <em>TPP1</em> Gene causes Neuronal Ceroid Lipofuscinosis Type 2 in a Family from Jammu and Kashmir-India

“…All these can be simulated in silico through MDS indicating the RMSD, RMSF, Rg and SASA profiles of a protein model. SASA analysis of a protein molecule can be highly essential for the functional annotation of a disease-associated variant, in the sense that pathogenicity is highly associated with the buried property of a protein molecule and should always be considered while performing MDS for a potentially pathogenic protein variant [57]. Since in our case study, SASA analysis revealed hTPP1 Q339 variant to be slightly buried than R339, the variation can be considered as potentially pathogenic in nature.…”

Specialization of the photoreceptor transcriptome bySrrm3-dependent microexons is required for outer segment maintenance and vision

“…S2 and Table S5). Out of 32 protein structures containing the microexon insertion site, the vast majority (96%) of those sites occurred in solvent accessible regions, namely regions with Relative Solvent Accessibility ≥ 20% 37 . Most insertion sites were mapped to unstructured loops (72%) rather than within structured helices (20%), sheets (4%), or turns (4%), further suggesting that RetMICs generally serve to modify protein surfaces instead of impacting overall protein folding.…”