Poster Presentation The 43rd Lorne Conference on Protein Structure and Function 2018

Mapping genotype-phenotype associations of nsSNPs in coiled-coil oligomerization domains of the human proteome. (#285)

Merridee A Wouters 1 , Kaavya A Mohanasundaram 2 , Mani P Grover 2 , Tamsyn M Crowley 2 , Andrzej Gocsinski 2
  1. Olivia Newton-John Cancer Research Institute, Heidelberg, VIC, Australia
  2. Deakin University, Geelong, Vic, Australia

Methods of assessing the impact of mutations and variants in protein coding regions are becoming increasingly needed as patient sequencing information piles up. Context information is important but is usually either not included or incorporated in only a generic way. Next generation methods that assess the impact of the amino acid substitution in a site-specific way are needed.

Here, 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.

  1. Mohansundaram et al Hum Mutat. 2017 Oct;38(10):1378-1393. doi: 10.1002/humu.23252. Epub 2017 Jun 23.