The Role of Structural Dynamics in Protein Function and Evolvability

Yusran Muthahari

Research output: ThesisThesis fully internal (DIV)

123 Downloads (Pure)

Abstract

To adapt to the new environmental changes, nature might evolve the protein functions by adjusting the protein dynamics during evolution. However, several questions remain unanswered: Can the modern proteins evolve from the same ancestral structural repertoire? And how are those proteins modulating their dynamics to specialize the new functions? In this thesis, we address such questions by investigating a large group of proteins harbouring a common primordial structure dubbed as the ‘cherry-core’ (CC). Structural and evolutionary analysis reveals that Cherry-core proteins (CCPs) have evolved from a common ancestor into several classes that differ concerning their C-termini. We further verified that insertions/deletions of secondary structure elements within the structural ‘core’ were combined with ‘modular’ additions of domains or secondary structure elements at the termini to confer distinct multi-tier structural dynamics the core. Such processes allow the diversification of function and ligand specificity during evolution. Using the combination of the ensemble- and the single-molecule level biophysical tools (i.e., single-molecule FRET, HDX-MS, and ITC), we confirmed that the extant Cherry-Core Proteins (CCPs) shift the conformational equilibria by utilizing simple additional structural elements to personify their functions. Our studies might advance the basis of protein design and further expand the currently available ‘evolvability theory’ to a non-fix length polypeptide, which possibly occurred during the long-evolutionary period.
Original languageEnglish
QualificationDoctor of Philosophy
Awarding Institution
  • University of Groningen
Supervisors/Advisors
  • Economou, Anastassios, Supervisor, External person
  • Cordes, Thorben, Supervisor
  • Roos, Wouter, Supervisor
  • Gkouridis, Giorgios, Co-supervisor
  • Lemke, Edward A, Assessment committee, External person
  • Rousseau, Frederic, Assessment committee, External person
  • Maglia, Giovanni, Assessment committee
  • Schymkowitz, Joost, Assessment committee, External person
Award date5-Feb-2021
Place of Publication[Groningen]
Publisher
DOIs
Publication statusPublished - 2021

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