Linked Life Data

21776984

Source:http://linkedlifedata.com/resource/pubmed/id/21776984

Statements in which the resource exists as a subject.
PredicateObject
rdf:type
lifeskim:mentions
pubmed:issue
33
pubmed:dateCreated
2011-8-16
pubmed:abstractText
Friedreich's ataxia (FRDA) is a progressive neurodegenerative disease associated with the loss of function of the protein frataxin (FXN) that results from low FXN levels due to a GAA triplet repeat expansion or, occasionally, from missense mutations in the FXN gene. Here biochemical and structural properties of FXN variants, including three FRDA missense mutations (N146K, Q148R, and R165C) and three related mutants (N146A, Q148G, and Q153A), were determined in an effort to understand the structural basis for the loss of function. In vitro assays revealed that although the three FRDA missense mutations exhibited similar losses of cysteine desulfurase and Fe-S cluster assembly activities, the causes for these activation defects were distinct. The R165C variant exhibited a k(cat)/K(M) higher than that of native FXN but weak binding to the NFS1, ISD11, and ISCU2 (SDU) complex, whereas the Q148R variant exhibited the lowest k(cat)/K(M) of the six tested FXN variants and only a modest binding deficiency. The order of the FXN binding affinities for the SDU Fe-S assembly complex was as follows: FXN > Q148R > N146A > Q148G > N146K > Q153A > R165C. Four different classes of FXN variants were identified on the basis of their biochemical properties. Together, these structure-function studies reveal determinants for the binding and allosteric activation of the Fe-S assembly complex and provide insight into how FRDA missense mutations are functionally compromised.
pubmed:language
eng
pubmed:journal
pubmed:citationSubset
IM
pubmed:chemical
pubmed:status
MEDLINE
pubmed:month
Aug
pubmed:issn
1520-4995
pubmed:author
pubmed:copyrightInfo
© 2011 American Chemical Society
pubmed:issnType
Electronic
pubmed:day
23
pubmed:volume
50
pubmed:owner
NLM
pubmed:authorsComplete
Y
pubmed:pagination
7265-74
pubmed:meshHeading
pubmed-meshheading:21776984-Allosteric Regulation, pubmed-meshheading:21776984-Carbon-Sulfur Lyases, pubmed-meshheading:21776984-Crystallography, X-Ray, pubmed-meshheading:21776984-Enzyme Activation, pubmed-meshheading:21776984-Friedreich Ataxia, pubmed-meshheading:21776984-Humans, pubmed-meshheading:21776984-Iron-Binding Proteins, pubmed-meshheading:21776984-Iron-Regulatory Proteins, pubmed-meshheading:21776984-Iron-Sulfur Proteins, pubmed-meshheading:21776984-Kinetics, pubmed-meshheading:21776984-Models, Molecular, pubmed-meshheading:21776984-Mutant Proteins, pubmed-meshheading:21776984-Mutation, Missense, pubmed-meshheading:21776984-Protein Binding, pubmed-meshheading:21776984-Protein Conformation, pubmed-meshheading:21776984-Structure-Activity Relationship, pubmed-meshheading:21776984-Sulfides
pubmed:year
2011
pubmed:articleTitle
Structure-function analysis of Friedreich's ataxia mutants reveals determinants of frataxin binding and activation of the Fe-S assembly complex.
pubmed:affiliation
Department of Chemistry, Texas A&M University, College Station, Texas 77842, USA.
pubmed:publicationType
Journal Article, Research Support, Non-U.S. Gov't