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Permanent URL to this publication: http://dx.doi.org/10.5167/uzh-35663

Feng, J; Lucchinetti, E; Enkavi, G; Wang, Y; Gehrig, P; Roschitzki, B; Schaub, M C; Tajkhorshid, E; Zaugg, K; Zaugg, M (2010). Tyrosine phosphorylation by Src within the cavity of the adenine nucleotide translocase 1 regulates ADP/ATP exchange in mitochondria. American Journal of Physiology: Cell Physiology, 298(3):C740-C748.

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Abstract

Phosphorylation of adenine nucleotide translocator 1 (ANT1) at residue Y194, which is part of the aromatic ladder located within the lumen of the carrier, critically regulates mitochondrial metabolism. Recent data support the concept that members of the Src family of nonreceptor tyrosine kinases are constitutively present in mitochondria and key to regulation of mitochondrial function. Herein, we demonstrate that site mutations of ANT1 (Y190-->F190, Y194-->F194) mimicking dephosphorylation of the aromatic ladder resulted in loss of oxidative growth and ADP/ATP exchange activity in respiration-incompetent yeast expressing mutant chimeric yN-hANT1. ANT1 is phosphorylated at Y194 by the Src family kinase members Src and Lck, and increased phosphorylation is tightly linked to reduced cell injury in preconditioned protected vs. unprotected cardiac mitochondria. Molecular dynamics simulations find the overall structure of the phosphorylated ANT1 stable, but with an increased steric flexibility in the region of the aromatic ladder, matrix loop m2, and four helix-linking regions. Combined with an analysis of the putative cytosolic salt bridge network, we reason that the effect of phosphorylation on transport is likely due to an accelerated transition between the main two conformational states (c<-->m) of the carrier during the transport cycle. Since "aromatic signatures" are typical for other mitochondrial carrier proteins with important biological functions, our results may be more general and applicable to these carriers.

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > Functional Genomics Center Zurich
08 University Research Priority Programs > Systems Biology / Functional Genomics
04 Faculty of Medicine > University Hospital Zurich > Clinic for Radiation Oncology
DDC:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2010
Deposited On:20 Sep 2010 08:54
Last Modified:17 Jul 2014 21:53
Publisher:American Physiological Society
ISSN:0363-6143
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:10.1152/ajpcell.00310.2009
PubMed ID:20007455
Citations:Web of Science®. Times Cited: 19
Google Scholar™
Scopus®. Citation Count: 22

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