The Role of Protein Complex Assembly in Dominant Mendelian Genetics Disorders

Speaker: Dr. Joseph Marsh, MRC Institute of Genetics & Molecular Medicine, University of Edinburgh
Host: Professor Kresten Lindorff-Larsen, Section for Biomolecular Sciences

Most proteins can assemble into complexes, and protein complex subunits are highly enriched in human disease mutations. I will discuss our recent work trying to understand the role of protein complexes in human genetic disease. First, I will focus on the dominant-negative effect, whereby a heterozygous mutation can cause an almost complete loss of function by sequestering wild type protein subunits within a non-functional complex. We have used systematic computational analyses to investigate the molecular determinants of dominant-negative mutations in comparison to other pathogenic mutations. We find that both protein quaternary structure and assembly patterns strongly influence the likelihood of observing a dominant-negative effect for a given gene. We also demonstrate that currently available phenotype predictors significantly underperform on dominant-negative mutations, likely due to the fact that they tend to be much milder at a protein structural level than other pathogenic mutations. Second, I will address the phenomenon of haploinsufficiency, in which the partial loss of function from a heterozygous mutation can cause disease. We show how this is often due to imbalances in protein complex stoichiometry, and that relative subunit expression levels, assembly pathways and transcriptional noise are all important properties for understanding assembly-mediated haploinsufficiency.