2. Academic Validation
  3. Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 (MMDS1): impact of a disease-causing Gly189Arg substitution on NFU1

Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 (MMDS1): impact of a disease-causing Gly189Arg substitution on NFU1

  • FEBS J. 2017 Nov;284(22):3838-3848. doi: 10.1111/febs.14271.
Nathaniel A Wesley 1,  Christine Wachnowsky 1 2,  Insiya Fidai 1 3,  J A Cowan 1 2 3
Affiliations

Affiliations

  • 1 Department of Chemistry and Biochemistry, The Ohio State University, Columbus, OH, USA.
  • 2 The Ohio State Biochemistry Program, The Ohio State University, Columbus, OH, USA.
  • 3 The Biophysics Graduate Program, The Ohio State University, Columbus, OH, USA.
PMID: 28906594 DOI: 10.1111/febs.14271
Abstract

Iron-sulfur (Fe/S) cluster-containing proteins constitute one of the largest protein classes, with highly varied function. Consequently, the biosynthesis of Fe/S clusters is evolutionarily conserved and mutations in intermediate Fe/S cluster scaffold proteins can cause disease, including multiple mitochondrial dysfunctions syndrome (MMDS). Herein, we have characterized the impact of defects occurring in the MMDS1 disease state that result from a point mutation (p.Gly189Arg) near the active site of NFU1, an Fe/S scaffold protein. In vitro investigation into the structure-function relationship of the Gly189Arg derivative, along with two other variants, reveals that substitution at position 189 triggers structural changes that increase flexibility, decrease stability, and alter the monomer-dimer equilibrium toward monomer, thereby impairing the ability of the Gly189X derivatives to receive an Fe/S cluster from physiologically relevant sources.

Keywords

NFU1; cluster exchange; iron-sulfur cluster; mitochondrial disease; protein stability.

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