The 1.8 Å crystal structure of ACTIBIND suggests a mode of action for T2 ribonucleases as antitumorigenic agents.
ACTIBIND and its human homologue RNASET2 are T2 ribonucleases (RNases). RNases are ubiquitous and efficient enzymes that hydrolyze RNA to 3' mononucleotides and also possess antitumorigenic and antiangiogenic activities. Previously, we have shown that ACTIBIND and RNASET2 bind actin and interfere with the cytoskeletal network structure, thereby inhibiting cell motility and invasiveness in cancer and in endothelial cells. We also showed that ACTIBIND binds actin in a molar ratio of 1:2. Here, we further characterize ACTIBIND and determine its crystal structure at 1.8 Å resolution, which enables us to propose two structural elements that create binding sites to actin. We suggest that each of these binding sites is composed of one cysteine residue and one conserved amino acid region. These binding sites possibly interfere with the cytoskeleton network structure and as such may be responsible for the antitumorigenic and antiangiogenic activities of ACTIBIND and its human analogue RNASET2.
Department of Clinical Biochemistry, Faculty of Health Sciences, Ben-Gurion University of the Negev, Beer Sheva 84105, Israel.
Marina
M
de Leeuw
Ana
A
González
Assaf
A
Lanir
Levava
L
Roiz
Patricia
P
Smirnoff
Betty
B
Schwartz
Oded
O
Shoseyov
Orna
O
Almog
D000199:Actins / Q000737:chemistry; D000595:Amino Acid Sequence; D020533:Angiogenesis Inhibitors / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001234:Aspergillus niger / Q000737:chemistry*; D001426:Bacterial Proteins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D001665:Binding Sites; D018360:Crystallography, X-Ray; D006023:Glycoproteins / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D006031:Glycosylation; D061307:Human Umbilical Vein Endothelial Cells / Q000187:drug effects; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D011487:Protein Conformation; D012260:Ribonucleases / Q000737:chemistry* / Q000302:isolation & purification / Q000494:pharmacology; D016415:Sequence Alignment; D025521:Tumor Suppressor Proteins / Q000737:chemistry
D000199:Actins; D020533:Angiogenesis Inhibitors; D001426:Bacterial Proteins; D006023:Glycoproteins; D025521:Tumor Suppressor Proteins; D012260:Ribonucleases; C425232:RNASET2 protein, human