title: ACTIN: Structure and Function : Towards an understanding of the conformational states of actin monomer and filament
creator: Splettstößer, Thomas
subject: ddc-570
subject: 570 Life sciences
description: Actin is a major structural protein of the eukaryotic cytoskeleton and plays a crucial role in cell motility, adhesion, morphology and intracellular transport. Its biologically active form is the filament (F-actin), which is assembled from monomeric G-actin. In this thesis, the structural characteristics of both G- and F-actin are studied using molecular dynamics simulations. First, the crystallographically-determined 'open' and 'closed' conformational states of Gactin are characterized in aqueous solution, with either ATP or ADP bound in the nucleotide binding pocket. In both nucleotide states, the open state closes in the absence of the actin-binding protein profilin, suggesting that the open state is not a stable conformation of isolated G-actin. Further, the simulations reveal the existence of a structurally well-defined, compact, 'superclosed' state of ATP-G-actin, as yet unseen crystallographically and absent in the ADP-Gactin simulations. The superclosed state resembles structurally the actin monomer in filament models and we suggest it to be the polymerization competent conformation of G-actin. Furthermore, we introduce a new actin filament model, the Holmes-2010 model that incorporates the global structure of a recently published model but in addition conserves internal stereochemistry. The improved quality of the Holmes-2010 model is apparent in a comparison made with other recent F-actin models using molecular dynamics simulation, monitoring a number of structural determinants. In addition, simulations of the model are carried out in states with both ATP or ADP bound and local hydrogen-bonding differences characterized. The results point to the significance of a direct interaction of GLN137 with ATP for activation of ATPase activity after the G-to-F-actin transition. The findings presented here may thus be a step towards a better understanding of the nucleotide-dependent structural differences of actin that lead to its functional differences.
date: 2010
type: Dissertation
type: info:eu-repo/semantics/doctoralThesis
type: NonPeerReviewed
format: application/pdf
identifier: https://archiv.ub.uni-heidelberg.de/volltextserverhttps://archiv.ub.uni-heidelberg.de/volltextserver/11535/1/Actin_structure_and_funtion.pdf
identifier: DOI:10.11588/heidok.00011535
identifier: urn:nbn:de:bsz:16-opus-115352
identifier:   Splettstößer, Thomas  (2010) ACTIN: Structure and Function : Towards an understanding of the conformational states of actin monomer and filament.  [Dissertation]     
relation: https://archiv.ub.uni-heidelberg.de/volltextserver/11535/
rights: info:eu-repo/semantics/openAccess
rights: http://archiv.ub.uni-heidelberg.de/volltextserver/help/license_urhg.html
language: eng