scholarly journals Tyrosine phosphorylation by Src within the cavity of the adenine nucleotide translocase 1 regulates ADP/ATP exchange in mitochondria

2010 ◽  
Vol 298 (3) ◽  
pp. C740-C748 ◽  
Author(s):  
Jianhua Feng ◽  
Eliana Lucchinetti ◽  
Giray Enkavi ◽  
Yi Wang ◽  
Peter Gehrig ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Cell Injury ◽  
Adenine Nucleotide ◽  
Salt Bridge ◽  
Mitochondrial Carrier ◽  
Transport Cycle ◽  
Dynamics Simulations ◽  
Adenine Nucleotide Translocator 1 ◽  
Mitochondrial Carrier Proteins ◽  
Nonreceptor Tyrosine Kinases

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.

Ion Pairing and Dielectric Decrement in Glycosaminoglycan Brushes

2020 ◽  
Author(s):  
James Sterling ◽  
Wenjuan Jiang ◽  
Wesley M. Botello-Smith ◽  
Yun L. Luo
Keyword(s):  
Molecular Dynamics ◽  
Ion Pairs ◽  
Mean Field ◽  
Salt Bridge ◽  
Ion Pairing ◽  
Donnan Potential ◽  
Mean Field Models ◽  
Ion Exclusion ◽  
Dynamics Simulations ◽  
Contact Ion Pairs

Molecular dynamics simulations of hyaluronic acid and heparin brushes are presented that show important effects of ion-pairing, water dielectric decrease, and co-ion exclusion. Results show equilibria with electroneutrality attained through screening and pairing of brush anionic charges by cations. Most surprising is the reversal of the Donnan potential that would be expected based on electrostatic Boltzmann partitioning alone. Water dielectric decrement within the brush domain is also associated with Born hydration-driven cation exclusion from the brush. We observe that the primary partition energy attracting cations to attain brush electroneutrality is the ion-pairing or salt-bridge energy associated with cation-sulfate and cation-carboxylate solvent-separated and contact ion pairs. Potassium and sodium pairing to glycosaminoglycan carboxylates and sulfates consistently show similar abundance of contact-pairing and solvent-separated pairing. In these crowded macromolecular brushes, ion-pairing, Born-hydration, and electrostatic potential energies all contribute to attain electroneutrality and should therefore contribute in mean-field models to accurately represent brush electrostatics.

Molecular Basis of Glucose Transport Mechanism in Plants

2019 ◽  
Author(s):  
Balaji Selvam ◽  
Ya-Chi Yu ◽  
Liqing Chen ◽  
Diwakar Shukla
Keyword(s):  
Molecular Dynamics ◽  
Free Energy ◽  
Molecular Dynamics Simulations ◽  
Conformational Changes ◽  
Transport Mechanism ◽  
Conformational Dynamics ◽  
Site Directed Mutagenesis ◽  
Free Energy Barrier ◽  
Transport Cycle ◽  
Dynamics Simulations

<p>The SWEET family belongs to a class of transporters in plants that undergoes large conformational changes to facilitate transport of sugar molecules across the cell membrane. However, the structures of their functionally relevant conformational states in the transport cycle have not been reported. In this study, we have characterized the conformational dynamics and complete transport cycle of glucose in OsSWEET2b transporter using extensive molecular dynamics simulations. Using Markov state models, we estimated the free energy barrier associated with different states as well as 1 for the glucose the transport mechanism. SWEETs undergoes structural transition to outward-facing (OF), Occluded (OC) and inward-facing (IF) and strongly support alternate access transport mechanism. The glucose diffuses freely from outside to inside the cell without causing major conformational changes which means that the conformations of glucose unbound and bound snapshots are exactly same for OF, OC and IF states. We identified a network of hydrophobic core residues at the center of the transporter that restricts the glucose entry to the cytoplasmic side and act as an intracellular hydrophobic gate. The mechanistic predictions from molecular dynamics simulations are validated using site-directed mutagenesis experiments. Our simulation also revealed hourglass like intermediate states making the pore radius narrower at the center. This work provides new fundamental insights into how substrate-transporter interactions actively change the free energy landscape of the transport cycle to facilitate enhanced transport activity.</p>

scholarly journals Presence of a Member of the Mitochondrial Carrier Family in Hydrogenosomes: Conservation of Membrane-Targeting Pathways between Hydrogenosomes and Mitochondria

2000 ◽  
Vol 20 (7) ◽  
pp. 2488-2497 ◽  
Author(s):  
Sabrina D. Dyall ◽  
Carla M. Koehler ◽  
Maria G. Delgadillo-Correa ◽  
Peter J. Bradley ◽  
Evelyn Plümper ◽  
...  
Keyword(s):  
Trichomonas Vaginalis ◽  
Protein Targeting ◽  
Phylogenetic Analyses ◽  
Eukaryotic Cell ◽  
Membrane Targeting ◽  
Carrier Proteins ◽  
Mitochondrial Carrier ◽  
Mitochondrial Carrier Family ◽  
Targeting Signal ◽  
Mitochondrial Carrier Proteins

ABSTRACT A number of microaerophilic eukaryotes lack mitochondria but possess another organelle involved in energy metabolism, the hydrogenosome. Limited phylogenetic analyses of nuclear genes support a common origin for these two organelles. We have identified a protein of the mitochondrial carrier family in the hydrogenosome ofTrichomonas vaginalis and have shown that this protein, Hmp31, is phylogenetically related to the mitochondrial ADP-ATP carrier (AAC). We demonstrate that the hydrogenosomal AAC can be targeted to the inner membrane of mitochondria isolated from Saccharomyces cerevisiae through the Tim9-Tim10 import pathway used for the assembly of mitochondrial carrier proteins. Conversely, yeast mitochondrial AAC can be targeted into the membranes of hydrogenosomes. The hydrogenosomal AAC contains a cleavable, N-terminal presequence; however, this sequence is not necessary for targeting the protein to the organelle. These data indicate that the membrane-targeting signal(s) for hydrogenosomal AAC is internal, similar to that found for mitochondrial carrier proteins. Our findings indicate that the membrane carriers and membrane protein-targeting machinery of hydrogenosomes and mitochondria have a common evolutionary origin. Together, they provide strong evidence that a single endosymbiont evolved into a progenitor organelle in early eukaryotic cells that ultimately give rise to these two distinct organelles and support the hydrogen hypothesis for the origin of the eukaryotic cell.

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