Structural and functional studies on GTPases involved in eukaryal translation initiation

by Bernhard Kuhle
Doctoral thesis
Date of Examination:2014-10-16
Date of issue:2015-06-05
Advisor:Prof. Dr. Ralf Ficner
Referee:Prof. Dr. Ralf Ficner
Referee:Prof. Dr. Marina Rodnina
Persistent Address: http://dx.doi.org/10.53846/goediss-5088

 

 

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Abstract

English

Translation, the process of mRNA-encoded protein biosynthesis, is one of the fundamental processes that are universally conserved in extant cellular life. In all its major stages, namely initiation, elongation, termination and recycling, translation depends on a dynamic interplay between the ribosome as the principle place of protein synthesis, mRNA, tRNAs and a number of accessory proteins called translation factors. A subgroup of these translation factors belongs to the universally conserved family of translational GTPases (trGTPases) that use the free energy of GTP hydrolysis to ensure the necessary speed and accuracy of protein synthesis on the ribosome. One of the most complex processes supported by trGTPases, namely by the eukaryal translation initiation factors 2 (eIF2) and 5B (eIF5B), is the intricate mechanism of cap-dependent translation initiation in eukaryal cells. The current thesis focuses on the structural and functional characterization of the trGTPases eIF2 and eIF5B. The first part of this thesis is dedicated to eIF2, a structurally unusually complex trGTPase that is responsible for the GTP-dependent delivery of the unique initiator tRNA to the ribosome, and the auxiliary initiation factors that regulate the guanine-nucleotide cycle of eIF2, namely the specialized GTPase activating protein (GAP) eIF5 and the guanine-nucleotide exchange factor (GEF) eIF2B. The second part of the thesis encompasses a structural and functional analysis of eIF5B, a universally conserved trGTPase that catalyzes ribosomal subunit joining in a GTP-dependent manner to form elongation-competent ribosomes.
Keywords: Translation; GTPases; Eukaryal translation inititation; Molecular Evolution
 
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