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ISSN: 2168-9652

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Research Article

Structural Effects of Leigh Syndrome Mutations on the Function of Human Mitochondrial Complex-I Q module

Tulika M Jaokar, Ranu Sharma and Suresh CG*
Division of Biochemical Sciences, National Chemical Laboratory, Dr Homi Bhabha Road, Pune-411008, India
*Corresponding Author : Suresh CG
Division of Biochemical Sciences
National Chemical Laboratory
Dr Homi Bhabha Road, Pune-411008, India
Tel: 91-20- 25902236
Fax: 91-20-25902648
E-mail: [email protected]
Received January 23, 2013; Accepted March 01, 2013; Published March 04, 2013
Citation: Jaokar TM, Sharma R, Suresh CG (2013) Structural Effects of Leigh Syndrome Mutations on the Function of Human Mitochondrial Complex-I Q module. Biochem Physiol S2:004. doi:10.4172/2168-9652.S2-004
Copyright: © 2013 Jaokar TM, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

The Q module of the human mitochondrial Complex-I (NADH:ubiquinone oxidoreductase) comprises of four core protein subunits: NDUFS2, NDUFS3, NDUFS7 and NDUFS8. It is an intermediate unit, connecting the dehydrogenase domain (N module) and the membrane arm (P module) of the L shaped mitochondrial Complex-I. Its role is to transfer electrons from N module to the P module. Mutations in the subunits of this module are reported to be associated with Leigh syndrome, a neurological genetic disorder. The Q module of human mitochondrial Complex-I is modelled based on the crystal structure of Thermus thermophilus Complex-I. The structural ramifications of the documented Leigh syndrome mutations were studied in silico, using molecular dynamics simulations. Although the mutations caused minimum perturbation to the overall secondary structure, the root mean square fluctuations of certain segments were substantial, especially those in the loop regions. The mutations affected the hydrogen bonded interactions, solvent accessible area, and the observed radius of gyration to various extents. The cumulative effect of all these changes on the formation of complex assembly is reflected in the observed unfavourable energy variations, instability of subunit association, and a reduced affinity for substrates, such as ubiquinone. Thus, our analysis indicates that Leigh syndrome mutations lead to formation of structurally and functionally defective complex, which in turn results in disease phenotype.

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