The utrophin-actin interface

Broderick, Michael James Francis (2005) The utrophin-actin interface. PhD thesis, University of Glasgow.

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The spectrin superfamily is a diverse group of proteins variously involved in cross- linking, bundling and binding to the F-actin cytoskeleton. These proteins are modular in nature and interaction with actin occurs, at least in part, via CH domain containing ABDs. The actin binding domains of the spectrin superfamily proteins are all very similar in overall structure however the functions of the individual proteins differ greatly. Utrophin is a member of the spectrin superfamily and has been used extensively to investigate and model the association of actin-binding domains with F- actin; however, much controversy exists as to whether binding occurs when the domain is in an open or a closed conformation. The data herein specifically investigates the importance of the utrophin ABD inter- CH domain linker to the conformation of the domain and how this domain associates with F-actin. We provide evidence that this particular region of the ABD is particularly sensitive to mutation and that the conformation of the domain when in solution cannot be altered by affecting the electrostatic environment surrounding the protein. It has been assumed previously that the utrophin ABD adopts a closed and compact configuration in solution similar to the fimbrin crystal structure conformation; however we present evidence that suggests this is not the case. It has been proposed that the utrophin ABD may open from this closed conformation to bind F-actin in a more open manner, we present data that demonstrates that opening of the domain is not essential to F-actin binding and that there is very little conformation change associated with the domain upon interaction with F-actin. It appears that the utrophin ABD can bind F actin in two conformations. This supports current models of utrophin ABD binding where interaction with F-actin occurs in either an open or closed conformation. The data presented here provides an interesting insight into the utrophin ABD/F-actin interaction and raises many questions regarding the evaluation of current binding models. Future research stemming from this work will serve to further the understanding of how utrophin and related actin-binding proteins interact with F-actin.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Colleges/Schools: College of Medical Veterinary and Life Sciences
Supervisor's Name: Winder, Prof. Steve
Date of Award: 2005
Depositing User: Mrs Monika Milewska-Fiertek
Unique ID: glathesis:2005-30889
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 11 Oct 2018 10:41
Last Modified: 11 Oct 2018 10:41
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