Nikolay A Alemasov1, Nikita V Ivanisenko2,3, Srinivasan Ramachandran4,5, Vladimir A Ivanisenko2. 1. The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russia. alemasov@bionet.nsc.ru. 2. The Federal Research Center Institute of Cytology and Genetics, The Siberian Branch of the Russian Academy of Sciences, 630090, Novosibirsk, Russia. 3. Novosibirsk State University, 630090, Novosibirsk, Russia. 4. Functional Genomics Unit, Council of Scientific and Industrial Research-Institute of Genomics and Integrative Biology (CSIR-IGIB), South Campus, New Delhi, 110025, India. 5. Academy of Scientific and Innovative Research, CSIR-IGIB, South Campus, New Delhi, 110025, India.
Abstract
BACKGROUND: So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure. RESULTS: In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres. CONCLUSIONS: The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.
BACKGROUND: So far, little is known about the molecular mechanisms of amyotrophic lateral sclerosis onset and progression caused by SOD1 mutations. One of the hypotheses is based on SOD1 misfolding resulting from mutations and subsequent deposition of its cytotoxic aggregates. This hypothesis is complicated by the fact that known SOD1 mutations of similar clinical effect could be distributed over the whole protein structure. RESULTS: In this work, a measure of hydrogen bond stability in conformational states was studied with elastic network analysis of 35 SOD1 mutants. Twenty-eight hydrogen bonds were detected in nine of 35 mutants with their stability being significantly different from that with the wild-type. These hydrogen bonds were formed by the amino acid residues known from the literature to be located in contact between SOD1 aggregates. Additionally, residues disposed between copper binding sites of both protein subunits were found from the models to form a stiff core, which can be involved in mechanical impulse transduction between these active centres. CONCLUSIONS: The modelling highlights that both stability of the copper binding site and stability of the dimer can play an important role in ALS progression.
Authors: Sai V Seetharaman; Duane D Winkler; Alexander B Taylor; Xiaohang Cao; Lisa J Whitson; Peter A Doucette; Joan S Valentine; Virgil Schirf; Borries Demeler; Mark C Carroll; Valeria C Culotta; P John Hart Journal: Biochemistry Date: 2010-07-13 Impact factor: 3.162
Authors: Jennifer Stine Elam; Alexander B Taylor; Richard Strange; Svetlana Antonyuk; Peter A Doucette; Jorge A Rodriguez; S Samar Hasnain; Lawrence J Hayward; Joan Selverstone Valentine; Todd O Yeates; P John Hart Journal: Nat Struct Biol Date: 2003-06
Authors: Megan W Bourassa; Hilda H Brown; David R Borchelt; Stefan Vogt; Lisa M Miller Journal: Front Aging Neurosci Date: 2014-06-16 Impact factor: 5.750