Faculty Opinions recommendation of Direct visualization of asymmetric adenine-nucleotide-induced conformational changes in MutL alpha.

Approximately one-third of proteins in the cell reside in the membrane. Mutations in membrane proteins can induce conformational changes and expose nonnative polar domains/residues to the lipid environment. The molecular effect of the resulting membrane stress is poorly defined. Adenine nucleotide translocase 1 (Ant1) is a mitochondrial inner membrane protein involved in ATP/ADP exchange. Missense mutations in the Ant1 isoform cause autosomal dominant progressive external ophthalmoplegia (adPEO), cardiomyopathy, and myopathy. The mechanism of the Ant1-induced pathologies is highly debated. Here we show that equivalent mutations in the yeast Aac2 protein cause protein misfolding. Misfolded Aac2 drastically affects the assembly and stability of multiple protein complexes in the membrane, which ultimately inhibits cell growth. Despite causing similar proteostatic damages, the adPEO- but not the cardiomyopathy/myopathy-type Aac2 proteins form large aggregates. The data suggest that the Ant1-induced diseases belong to protein misfolding disorders. Protein homeostasis is subtly maintained on the mitochondrial inner membrane and can be derailed by the misfolding of one single protein with or without aggregate formation. This finding could have broad implications for understanding other dominant diseases (e.g., retinitis pigmentosa) caused by missense mutations in membrane proteins.

Download Full-text

Mobilization of Adenine Nucleotide Translocators as Molecular Bases of the Biochemical Threshold Effect Observed in Mitochondrial Diseases

Journal of Biological Chemistry ◽

10.1074/jbc.m314259200 ◽

2004 ◽

Vol 279 (19) ◽

pp. 20411-20421 ◽

Cited By ~ 37

Author(s):

Benjamin Faustin ◽

Rodrigue Rossignol ◽

Christophe Rocher ◽

Giovanni Bénard ◽

Monique Malgat ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Conformational Changes ◽

Adenine Nucleotide ◽

Mitochondrial Diseases ◽

Permeability Transition Pore ◽

Permeability Transition ◽

Threshold Effect ◽

Adenine Nucleotide Translocator ◽

Flux Increase ◽

Molecular Bases

The existence of a biochemical threshold effect in the metabolic expression of oxidative phosphorylation deficiencies has considerable implications for the understanding of mitochondrial bioenergetics and the study of mitochondrial diseases. However, the molecular bases of this phenomenon remain unclear. We report here a new mechanism to explain this threshold effect, based on a reserve of enzymes not initially participating in the respiratory rate that can be activated either to respond to a flux increase or to compensate for a defect induced by a mutation. We show that this mobilization occurs through 1) the assembly of inactive adenine nucleotide translocator isoform 1 subunits into oligomeric active carriers or 2) conformational changes in the adenine nucleotide translocator isoform 1 in a permeability transition pore-like structure. We discuss how these transitions are sensitive to the steady state of oxidative phosphorylation functioning or tissue and analyze their consequences on the threshold effect.

Download Full-text

Influence of Calcium Ions on the Plant Cell Surface: Membrane Fusions and Conformational Changes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100050780 ◽

1974 ◽

Vol 32 ◽

pp. 154-155

Author(s):

D. James Morré ◽

Charles E. Bracker ◽

William J. VanDerWoude

Keyword(s):

Cell Wall ◽

Cell Surface ◽

Conformational Changes ◽

Calcium Ions ◽

Surface Membrane ◽

Carboxyl Groups ◽

Cross Linking ◽

Ultrastructural Evidence ◽

Glycine Max L ◽

Wall Extensibility

Calcium ions in the concentration range 5-100 mM inhibit auxin-induced cell elongation and wall extensibility of plant stems. Inhibition of wall extensibility requires that the tissue be living; growth inhibition cannot be explained on the basis of cross-linking of carboxyl groups of cell wall uronides by calcium ions. In this study, ultrastructural evidence was sought for an interaction of calcium ions with some component other than the wall at the cell surface of soybean (Glycine max (L.) Merr.) hypocotyls.

Download Full-text

Role of spectrin in membrane fusion and in shape change of human erythrocyte ghost

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100082509 ◽

1978 ◽

Vol 36 (2) ◽

pp. 328-329

Author(s):

Hideo Hayashi ◽

Yoshikazu Hirai ◽

John T. Penniston

Keyword(s):

Conformational Changes ◽

Human Erythrocyte ◽

Shape Change ◽

Membrane Surface ◽

Slight Modification ◽

Active Role ◽

Main Role ◽

Bank Blood ◽

Human Erythrocyte Ghost

Spectrin is a membrane associated protein most of which properties have been tentatively elucidated. A main role of the protein has been assumed to give a supporting structure to inside of the membrane. As reported previously, however, the isolated spectrin molecule underwent self assemble to form such as fibrous, meshwork, dispersed or aggregated arrangements depending upon the buffer suspended and was suggested to play an active role in the membrane conformational changes. In this study, the role of spectrin and actin was examined in terms of the molecular arrangements on the erythrocyte membrane surface with correlation to the functional states of the ghosts.Human erythrocyte ghosts were prepared from either freshly drawn or stocked bank blood by the method of Dodge et al with a slight modification as described before. Anti-spectrin antibody was raised against rabbit by injection of purified spectrin and partially purified.

Download Full-text

Direct visualization of phase-separated domains in lipid membranes

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100082315 ◽

1978 ◽

Vol 36 (2) ◽

pp. 290-291

Author(s):

S. W. Hui ◽

T. P. Stewart

Keyword(s):

Lipid Membranes ◽

Structural Information ◽

Freeze Fracture ◽

Biological Molecules ◽

Vacuum Drying ◽

Direct Visualization ◽

X Ray Diffraction ◽

Electron Microscopic ◽

X Ray ◽

Hydrocarbon Chains

Direct electron microscopic study of biological molecules has been hampered by such factors as radiation damage, lack of contrast and vacuum drying. In certain cases, however, the difficulties may be overcome by using redundent structural information from repeating units and by various specimen preservation methods. With bilayers of phospholipids in which both the solid and fluid phases co-exist, the ordering of the hydrocarbon chains may be utilized to form diffraction contrast images. Domains of different molecular packings may be recgnizable by placing properly chosen filters in the diffraction plane. These domains would correspond to those observed by freeze fracture, if certain distinctive undulating patterns are associated with certain molecular packing, as suggested by X-ray diffraction studies. By using an environmental stage, we were able to directly observe these domains in bilayers of mixed phospholipids at various temperatures at which their phases change from misible to inmissible states.

Download Full-text

Pinocytotic-Like Forms of Mitochondria From Rat Anterior Pituitary

Proceedings, annual meeting, Electron Microscopy Society of America ◽

10.1017/s0424820100100470 ◽

1968 ◽

Vol 26 ◽

pp. 146-147

Author(s):

Burton B. Silver

Keyword(s):

Electron Micrographs ◽

Conformational Changes ◽

Anterior Pituitary ◽

Dynamic State ◽

Surrounding Cell ◽

The Matrix ◽

The Moment ◽

Cell Medium ◽

Sectioned Tissue ◽

State Of Activity

Sectioned tissue rarely indicates evidence of what is probably a highly dynamic state of activity in mitochondria which have been reported to undergo a variety of movements such as streaming, divisions and coalescence. Recently, mitochondria from the rat anterior pituitary have been fixed in a variety of configurations which suggest that conformational changes were occurring at the moment of fixation. Pinocytotic-like vacuoles which may be taking in or expelling materials from the surrounding cell medium, appear to be forming in some of the mitochondria. In some cases, pores extend into the matrix of the mitochondria. In other forms, the remains of what seems to be pinched off vacuoles are evident in the mitochondrial interior. Dense materials, resembling secretory droplets, appear at the junction of the pores and the cytoplasm. The droplets are similar to the secretory materials commonly identified in electron micrographs of the anterior pituitary.

Download Full-text