Actin, troponin C, Alzheimer amyloid precursor protein and pro-interleukin 1 beta as substrates of the protease from human immunodeficiency virus.
We show here for the first time that actin, troponin C, Alzheimer amyloid precursor protein (AAP), and pro-interleukin 1 beta (pro-IL-1 beta), are substrates of the protease encoded by the human immunodeficiency virus (HIV) type-1. As has been seen in other non-viral protein substrates of the HIV protease, the presence of Glu residues in the P2' position appears to play an important role in substrate recognition. Three of the four bonds cleaved in actin, two of the three in troponin C, and all of the bonds hydrolyzed in AAP and pro-IL-1 beta have a P2' Glu residue. In fact, Glu residues are accommodated in all positions from P4 to P4' surrounding the scissile bond in substrates of the HIV proteases, and as many as 4 adjacent Glu residues were seen in one of the bonds cleaved in AAP. This study of non-viral protein substrates has also revealed unexpected amino acids such as Gly, Arg, and Glu in the scissile bond itself rather than the more conventional hydrophobic amino acids. The HIV-2 protease hydrolyzed actin in a manner similar to that of the HIV-1 enzyme, but its cleavage of troponin C was distinct in that it split a bond adjacent to a triplet of Glu residues in P2, P3, and P4 that was refractory to the HIV-1 enzyme. Documentation of cleavage sites in the several important cellular proteins noted above has extended our understanding of the features in a substrate that are recognized by these multi sub-site proteases of retroviral maturation. Moreover, the present work adds to an accumulating body of evidence which demonstrates that these enzymes can damage crucial structural and regulatory cellular proteins if ever their activity is expressed outside the viral particle itself.
Tomasselli
A G
AG
Upjohn Laboratories, Upjohn Company, Kalamazoo, Michigan 49001.
Hui
J O
JO
Adams
L
L
Chosay
J
J
Lowery
D
D
Greenberg
B
B
Yem
A
A
Deibel
M R
MR
Zürcher-Neely
H
H
Heinrikson
R L
RL
D000199:Actins / Q000378:metabolism*; D000595:Amino Acid Sequence; D016229:Amyloid beta-Peptides / Q000378:metabolism*; D016564:Amyloid beta-Protein Precursor; D002851:Chromatography, High Pressure Liquid; D004591:Electrophoresis, Polyacrylamide Gel; D016333:HIV Protease / Q000378:metabolism*; D015497:HIV-1 / Q000201:enzymology; D015498:HIV-2 / Q000201:enzymology; D006868:Hydrolysis; D007375:Interleukin-1 / Q000378:metabolism*; D008969:Molecular Sequence Data; D011498:Protein Precursors / Q000378:metabolism*; D013379:Substrate Specificity; D014336:Troponin / Q000378:metabolism*; D019209:Troponin C
D000199:Actins; D016229:Amyloid beta-Peptides; D016564:Amyloid beta-Protein Precursor; D007375:Interleukin-1; D011498:Protein Precursors; D014336:Troponin; D019209:Troponin C; C043830:interleukin 1 precursor; D016333:HIV Protease