Mitochondrial alterations induced by the p13II protein of human T-cell leukemia virus type 1. Critical role of arginine residues.
Human T-cell leukemia virus type 1 encodes a number of "accessory" proteins of unclear function; one of these proteins, p13(II), is targeted to mitochondria and disrupts mitochondrial morphology. The present study was undertaken to unravel the function of p13(II) through (i) determination of its submitochondrial localization and sequences required to alter mitochondrial morphology and (ii) an assessment of the biophysical and biological properties of synthetic peptides spanning residues 9-41 (p13(9-41)), which include the amphipathic mitochondrial-targeting sequence of the protein. p13(9-41) folded into an alpha helix in micellar environments. Fractionation and immunogold labeling indicated that full-length p13(II) accumulates in the inner mitochondrial membrane. p13(9-41) induced energy-dependent swelling of isolated mitochondria by increasing inner membrane permeability to small cations (Na(+), K(+)) and released Ca(2+) from Ca(2+)-preloaded mitochondria. These effects as well as the ability of full-length p13(II) to alter mitochondrial morphology in cells required the presence of four arginines, forming the charged face of the targeting signal. The mitochondrial effects of p13(9-41) were insensitive to cyclosporin A, suggesting that full-length p13(II) might alter mitochondrial permeability through a permeability transition pore-independent mechanism, thus distinguishing it from the mitochondrial proteins Vpr and X of human immunodeficiency virus type 1 and hepatitis B virus, respectively.
D'Agostino
Donna M
DM
Department of Oncology and Surgical Sciences, University of Padova, via Gattamelata 64, 35128 Padua, Italy.
Ranzato
Laura
L
Arrigoni
Giorgio
G
Cavallari
Ilaria
I
Belleudi
Francesca
F
Torrisi
Maria Rosaria
MR
Silic-Benussi
Micol
M
Ferro
Tiziana
T
Petronilli
Valeria
V
Marin
Oriano
O
Chieco-Bianchi
Luigi
L
Bernardi
Paolo
P
Ciminale
Vincenzo
V
D000595:Amino Acid Sequence; D001120:Arginine; D015368:Human T-lymphotropic virus 1 / Q000737:chemistry*; D006801:Humans; D008564:Membrane Potentials; D008928:Mitochondria / Q000737:chemistry / Q000502:physiology; D008933:Mitochondrial Swelling; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000502:physiology; D017510:Protein Folding; D017433:Protein Structure, Secondary; D012191:Retroviridae Proteins / Q000032:analysis / Q000737:chemistry / Q000502:physiology*; D013329:Structure-Activity Relationship
D010446:Peptide Fragments; D012191:Retroviridae Proteins; C072813:rof protein, Human T-lymphotropic virus 1; D001120:Arginine