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Dynamics of the SOD1 functional loops – disorder and fluctuations of the apo state can both be triggered and prevented by metallation
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
Stockholms universitet, Naturvetenskapliga fakulteten, Institutionen för biokemi och biofysik.
(Engelska)Manuskript (preprint) (Övrigt vetenskapligt)
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi
Identifikatorer
URN: urn:nbn:se:su:diva-107540OAI: oai:DiVA.org:su-107540DiVA, id: diva2:748211
Tillgänglig från: 2014-09-18 Skapad: 2014-09-18 Senast uppdaterad: 2014-09-23
Ingår i avhandling
1. Zinc in folding and misfolding of SOD1: Implications for ALS
Öppna denna publikation i ny flik eller fönster >>Zinc in folding and misfolding of SOD1: Implications for ALS
2014 (Engelska)Doktorsavhandling, sammanläggning (Övrigt vetenskapligt)
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease causing degeneration of upper and lower motor neurons. Most ALS cases are sporadic; only 6% are associated with mutations in Cu, Zn superoxide dismutase (SOD1). It is believed, however, that sporadic and familiar forms of ALS share a common mechanism, where SOD1 plays an important role: SOD1 knockout mice do not develop ALS, whereas the overexpression of human SOD1 in mice produces ALS-like symptoms. Increasing evidence suggest that the SOD1 structure gains cytotoxic properties, but detailed description of the toxic species is missing. This thesis work is focused on understanding how structural and dynamic properties of SOD1 change along its folding free-energy landscape and indicates the structural hot-spots from where the cytotoxic species may originate. Thus, binding of the zinc controls folding, stability and turnover of SOD1: (i) miscoordination of Zn2+ by the Cu-ligands speeds up folding of the SOD1 core structure, however, it stabilizes SOD1 in a state where both active-site loops IV and VII are unfolded, (ii) coordination of Zn2+ in the Zn-site, induces the folding of loop VII and stabilizes the native and  functional fold of both active-site loops and (iii) the tremendous stability gain due to Zn-site metallation corresponds to a folded state’s lifetime of  > 100 years, thus the cellular lifetime of SOD1 is likely controlled by Zn2+ release, which again is coupled to opening of active-site loops. Hence the active-site loops IV and VII stand out as critical and floppy parts of the SOD1 structure. Moreover, a number of ALS-associated mutations, benign to apo-SOD1 stability, are shown here to affect integrity of active-site loops in holo-SOD1, which, in turn, increases population of SOD1 species with these loops disorganized. Finally, the close relation between SOD1 and Zn2+ can also act in the reverse direction: a perturbed folding free-energy landscape of SOD1 can disturb Zn2+ homeostasis.

Ort, förlag, år, upplaga, sidor
Stockholm: Department of Biochemistry and Biophysics, Stockholm University, 2014. s. 64
Nyckelord
protein stability, protein misfolding, local unfolding, metal binding, energy landscape, protein disease, amyotrophic lateral sclerosis
Nationell ämneskategori
Biologiska vetenskaper
Forskningsämne
biokemi
Identifikatorer
urn:nbn:se:su:diva-107543 (URN)978-91-7447-939-3 (ISBN)
Disputation
2014-10-21, Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B, Stockholm, 10:00 (Engelska)
Opponent
Handledare
Anmärkning

At the time of the doctoral defense, the following papers were unpublished and had a status as follows: Paper 3: Manuscript. Paper 4: Manuscript.

Tillgänglig från: 2014-09-29 Skapad: 2014-09-18 Senast uppdaterad: 2014-11-21Bibliografiskt granskad

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Leinartaité, LinaOliveberg, Mikael
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Institutionen för biokemi och biofysik
Biologiska vetenskaper

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