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Understanding the molecular basis for multiple mitochondrial dysfunctions syndrome 1 ( MMDS 1): impact of a disease‐causing Gly189Arg substitution on NFU 1
Author(s) -
Wesley Nathaniel A.,
Wachnowsky Christine,
Fidai Insiya,
Cowan J. A.
Publication year - 2017
Publication title -
the febs journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 204
eISSN - 1742-4658
pISSN - 1742-464X
DOI - 10.1111/febs.14271
Subject(s) - scaffold protein , point mutation , function (biology) , mutation , cluster (spacecraft) , dimer , monomer , chemistry , loss function , protein structure , biology , biochemistry , biophysics , computational biology , genetics , microbiology and biotechnology , gene , phenotype , signal transduction , computer science , organic chemistry , programming language , polymer
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 MMDS 1 disease state that result from a point mutation (p.Gly189Arg) near the active site of NFU 1, 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.