A lysine-to-arginine change found in natural alleles of the human T-cell lymphotropic/leukemia virus type 1 p12(I) protein greatly influences its stability.
The HTLV-1 singly spliced open reading frame I protein, p12(I), is highly unstable and appears to be necessary for persistent infection in rabbits. Here we demonstrate that p12(I) forms dimers through two putative leucine zipper domains and that its stability is augmented by specific proteasome inhibitors. p12(I) is ubiquitylated, and mutations of its unique carboxy-terminus lysine residue to an arginine greatly enhance its stability. Interestingly, analysis of 53 independent HTLV-1 strains revealed that the natural p12(I) alleles found in ex vivo samples of tropical spastic paraparesis-HTLV-1-associated myelopathy patients contain a Lys at position 88 in some cases, whereas arginine is consistently found at position 88 in HTLV-1 strains from all adult T-cell leukemia-lymphoma (ATLL) cases and healthy carriers studied. This apparent segregation of different alleles in tropical spastic paraparesis-HTLV-associated myelopathy and ATLL or healthy carriers may be relevant in vivo, since p12(I) binds the interleukin-2 receptor beta and gammac chains, raising the possibility that the two natural alleles might affect differently the regulation of these molecules.
Trovato
R
R
Basic Research Laboratory, National Cancer Institute, Bethesda, Maryland 20892, USA.
Mulloy
J C
JC
Johnson
J M
JM
Takemoto
S
S
de Oliveira
M P
MP
Franchini
G
G
D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001120:Arginine / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D001665:Binding Sites; D002353:Carrier State; D003546:Cysteine Endopeptidases / Q000378:metabolism; D015368:Human T-lymphotropic virus 1 / Q000235:genetics* / Q000378:metabolism / Q000502:physiology*; D006801:Humans; D016350:Leucine Zippers; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000821:virology*; D008239:Lysine / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D008969:Molecular Sequence Data; D009097:Multienzyme Complexes / Q000378:metabolism; D009856:Oncogene Proteins, Viral / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D015493:Paraparesis, Tropical Spastic / Q000821:virology*; D046988:Proteasome Endopeptidase Complex; D014157:Transcription Factors; D014452:Ubiquitins; D054334:Viral Regulatory and Accessory Proteins
D009097:Multienzyme Complexes; D009856:Oncogene Proteins, Viral; D014157:Transcription Factors; D014452:Ubiquitins; D054334:Viral Regulatory and Accessory Proteins; C084305:p12I protein, Human T-lymphotropic virus 1; D001120:Arginine; D003546:Cysteine Endopeptidases; D046988:Proteasome Endopeptidase Complex; D008239:Lysine