Mapping genotype–phenotype associations of nsSNPs in coiled-coil oligomerization domains of the human proteome

5 years ago

Mapping genotype–phenotype associations of nsSNPs in coiled-coil oligomerization domains of the human proteome

Merridee A Wouters, Andrzej Goscinski, Mani P Grover, Tamsyn M Crowley, Kaavya A Mohanasundaram

We assessed the impact of disease mutations (DMs) versus polymorphisms (PYs) in coiled-coil (CC) domains in UniProt by modeling the structural and functional impact of variants in silico with the CC prediction program Multicoil. The structural impact of variants was evaluated with respect to three main metrics: the oligomerization score—to determine whether the variant is stabilizing or destabilizing—the oligomerization state, and the register-specific score. The functional impact was queried indirectly in several ways. First, we examined marginally stable CCs that were either stabilized or destabilized by the variant. Second, we looked for variants that altered the register of the wild-type CC near wild-type irregularities of likely functional importance, such as skips and stammers. Third, we searched for variants that altered the oligomerization state of the CC. DMs tended to be more destabilizing than PYs; but interestingly, PYs were more frequently associated with predicted changes in the oligomerization state. The functional impact was also queried by testing the association of CC variants with multiple phenotypes, that is, pleiotropy. Mutations in CC regions of proteins cause 155 different phenotypes and are more frequently associated with pleiotropy than proteins in general. Importantly, the CC region itself often encodes the pleiotropy. We assessed the impact of disease mutations versus polymorphisms in coiled-coil domains by modelling the impact of variants in silico with the coiled-coil prediction program Multicoil. Disease mutations tended to be more destabilising while polymorphisms caused more subtle effects, causing changes in oligomerization state and in irregularities of the heptad repeat that may influence the dynamic behaviour of the CC. Mutations in coiled-coils cause 155 different phenotypes and are more frequently associated with pleiotropy than proteins in general.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/humu.23252