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Discovering evolutionary innovations by assessing variation and natural selection in protein tandem repeats

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  • Projektleiter/in: Dr. Maria Anisimova
  • Projektteam: Dr. Spencer Bliven, Prof. Dr. Andreas Pluckthun
  • Projektvolumen: CHF 180'000
  • Projektstatus: laufend
  • Drittmittelgeber: EU und andere Internationale Programme

Beschreibung

Tandem repeats (TRs) are abundant in proteomes across all kingdoms of life. Having an impressive variety of
sizes, structures and functions, TRs often offer enhanced binding properties and are associated with disease
and immunity related functions. While mechanisms generating protein TRs are poorly understood, natural
selection contributes to shaping their evolution, and TR expansion may be linked to the origin of novel genes.
Specific combinations of TR units with point mutations/indels are able to ensure desirable protein properties.
Indeed, the design-ability of domain TRs has been successfully exploited in bioengineering. However, the
experimental search for optimal TR configurations is difficult/inefficient due to the huge number of possible
combinations. We will address this by modeling the evolution and natural selection in naturally observed proteins
with domain TRs. Combined with annotations of structure, function and protein-protein interactions, we will
pinpoint the naturally occuring evolutionary innovations, i.e., TR configurations that have been fixed by selection
due to adaptive benefits. These predictions can serve as testable hypotheses in protein engineering
experiments, allowing to narrow down the search to combinations with optimal properties according to the
natural evolution history. For ankyrin and armadillo repeats, employed to design medically relevant proteins,
specific recommendations will be made for further experimental testing.