Amino acids are the building blocks of proteins. Just twenty different amino acids are strung together in different orders – like beads – to build all the proteins in living organisms. When a single type of amino acid is found consecutively within a protein, this is known as a homorepeat. Abnormal variation in the length of amino acid homorepeats has long been known to be associated with disease, such as Huntington’s. Yet proteins containing amino acid homorepeats are common across eukaryotes and such proteins can have diverse functions. New work spearheaded by Sreenivas Chavali in Madan Babu’s group in the LMB’s Structural Studies Division has shown that homorepeat-containing proteins (HRPs) are not always bad, and can be beneficial to organisms and allow rapid evolution, provided the protein is tightly regulated.
The team of scientists including Balaji Santhanam at the LMB and Kevin Verstrepen’s group at the University of Leuven and VIB, Belgium identified and analysed HRPs and nonHRPs (proteins without amino acid homorepeats) in budding yeast. Deletion of non-essential HRPs, compared with nonHRPs, made the cells sensitive to a higher number of chemical insults and stresses, suggesting that homorepeats are found in proteins whose presence protects cells against environmental disturbances. In addition, use of a combination of computational and experimental techniques revealed that homorepeats are enriched in proteins that affect diverse phenotypes. To understand the molecular basis of this observation, Madan’s group examined interaction networks and found that HRPs tend to have a higher number of genetic and protein interactions, often acting as ‘hubs’ to link diverse biological processes. This is because the presence of homorepeats in proteins influences their spatial organisation within the cell, and facilitates interactions with other proteins.
Given the ability of HRPs to mediate diverse functions and to interact with many distinct protein partners, Madan’s group went on to study how HRPs are regulated. The activity of HRPs is highly regulated in cells, which likely minimises their potentially damaging effects – such as their ability to aggregate. Moreover, evolutionary studies showed that whilst homorepeats can arise in any protein, they are more likely to be retained in proteins that are already tightly regulated. Further analysis indicated that the presence of homorepeats facilitates the accumulation of amino acid substitutions at other, often functionally important, sites in the protein. Thus, homorepeats help to drive protein divergence, providing organisms with the raw material for variation and the potential to rewire interaction networks, facilitating rapid evolution and adaptation.
This is the largest and most comprehensive published study on homorepeat-containing proteins. It opens new horizons for answering questions about how proteins with unusual features, such as amino acid homorepeats, are involved in organising processes in cells, influencing organism phenotypes and contributing to evolution.
This work was funded by the MRC, the European Molecular Biology Organisation, Human Frontier Science Program, ERASysBio+, Marie Curie Actions, Cancer Research UK and the Lister Institute Prize.
Paper in Nature Structural & Molecular Biology
Madan Babu’s group page
Kevin Verstrepen’s group page