Correlating disease-related mutations to their effect on protein stability: A large-scale analysis of the human proteome

• Published in: Human mutation Vol. 32; no. 10; pp. 1161 - 1170
• Main Authors: Casadio, Rita, Vassura, Marco, Tiwari, Shalinee, Fariselli, Piero, Luigi Martelli, Pier
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-10-2011; Hindawi Limited
• Subjects: Amino acid sequence; Amino Acid Substitution; Computational Biology; Computer applications; Data processing; Databases, Protein; disease; Genetic Association Studies; Humans; Mutation; Mutation, Missense; Polymorphism, Genetic; probability; probability, protein stability; Protein Stability; Protein structure; Proteome - genetics; SAP annotation; SAP protein; Thermodynamics
• ISSN: 1059-7794; 1098-1004; 1098-1004
• DOI: 10.1002/humu.21555

Single residue mutations in proteins are known to affect protein stability and function. As a consequence, they can be disease associated. Available computational methods starting from protein sequence/structure can predict whether a mutated residue is or not disease associated and whether it is promoting instability of the protein‐folded structure. However, the relationship among stability changes in proteins and their involvement in human diseases still needs to be fully exploited. Here, we try to rationalize in a nutshell the complexity of the question by generalizing over information already stored in public databases. For each single aminoacid polymorphysm (SAP) type, we derive the probability of being disease‐related (Pd) and compute from thermodynamic data three indexes indicating the probability of decreasing (P−), increasing (P+), and perturbing the protein structure stability (Pp). Statistically validated analysis of the different P/Pd correlations indicate that Pd best correlates with Pp. Pp/Pd correlation values are as high as 0.49, and increase up to 0.67 when data variability is taken into consideration. This is indicative of a medium/good correlation among Pd and Pp and corroborates the assumption that protein stability changes can also be disease associated at the proteome level. Hum Mutat 32:1161–1170, 2011. ©2011 Wiley‐Liss, Inc.