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Impaired transport of nucleotides in a mitochondrial carrier explains severe human genetic diseases.

Abstract：

:The mitochondrial ADP/ATP carrier (AAC) is a prominent actor in the energetic regulation of the cell, importing ADP into the mitochondria and exporting ATP toward the cytoplasm. Severe genetic diseases have been ascribed to specific mutations in this membrane protein. How minute, well-localized modifications of the transporter impact the function of the mitochondria remains, however, largely unclear. Here, for the first time, the relationship between all documented pathological mutations of the AAC and its transport properties is established. Activity measurements combined synergistically with molecular-dynamics simulations demonstrate how all documented pathological mutations alter the binding affinity and the translocation kinetics of the nucleotides. Throwing a bridge between the pathologies and their molecular origins, these results reveal two distinct mechanisms responsible for AAC-related genetic disorders, wherein the mutations either modulate the association of the nucleotides to the carrier by modifying its electrostatic signature or reduce its conformational plasticity.

journal_name

ACS Chem Biol

journal_title

ACS chemical biology

authors

Ravaud S,Bidon-Chanal A,Blesneac I,Machillot P,Juillan-Binard C,Dehez F,Chipot C,Pebay-Peyroula E

doi

10.1021/cb300012j

subject

Has Abstract

pub_date

2012-07-20 00:00:00

pages

1164-9

issue

7

eissn

1554-8929

issn

1554-8937

journal_volume

7

pub_type

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