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Title: Structural studies on actin : gelsolin segment 1 complexes
Author: Morton, Walter Manfred
Awarding Body: University of Edinburgh
Current Institution: University of Edinburgh
Date of Award: 1999
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Prevention of actin polymerisation is lethal to cells. Latrunculin A, a toxic metabolite of Red Sea sponges, binds tightly to actin monomers (KD 1 0.2μM) and prevents those monomers participating in actin filament formation, disrupting the actin cytoskeleton. This thesis investigates the structural consequences of gelsolin segment 1 binding to actin isoforms, as well as the structural control gelsolin segment 1 exerts on actin preventing nucleotide exchange. To this end the crystal structures of gelsolin segment 1 on its own and in complex with β-actin and α-actin were solved at 100 Kelvin to a resolution of 2.2Å, 2.2Å, and 2.3Å respectively. Furthermore the marine toxin latrunculin A was successfully soaked into crystals of α-actin: gelsolin segment 1 and the structure determined at 100 Kelvin and to a resolution of 1.0Å. The refined structures were compared with each other and with previously crystal structures of gelsolin segment 1 and actin. The investigations revealed conformational differences between the structures of gelsolin segment 1 crystallised on its own, in its complex with actin, and in the published horse gelsolin crystal structure. The structure determination of α- and β-actin complexed to gelsolin segment 1 resulted in actin displaying a different conformation than that found in the complex with profilin, particularly in respect to the actin subdomain 2. The binding of latrunculin A just above the actin ATP-binding site induces changes along the protein chain of the actin subdomain 4. Other changes to the actin structure are located in subdomain 2.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available