Crystal structure of bovine angiogenin at 1.5-A resolution.

Acharya, K. Ravi; Shapiro, Robert; Riordan, James; Vallée, Bert L.

doi:10.1073/pnas.92.7.2949

Cited by 49 publications

(55 citation statements)

References 33 publications

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“…As observed in the structures of other Ang family members (29,42,71), the B 1 subsite is obstructed by the C-terminal segment (residues 115-120 of mAng-4), and a major rearrangement of the C-terminal segment is the only reasonable means by which RNA substrates can bind productively (Figure 8a). Glu115 mimics part of a pyrimidine ring, spanning the B 1 subsite in the manner of its hAng and mAng-1 counterparts (Gln117 and Glu116, respectively) to engage in hydrogen bonds with main and side chain atoms of Thr43.…”

Section: Resultsmentioning

confidence: 95%

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,

et al. 2007

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Murine angiogenin-4 (mAng-4) is a member of the pancreatic ribonuclease superfamily that is expressed in some endodermally derived organs. We now show that mAng-4 is angiogenic using a thoracic aorta assay never before applied to the angiogenins. mAng-4, human angiogenin (hAng), and murine angiogenin-1 (mAng-1) stimulate the proliferation of IGR1 melanoma cells but do not stimulate the proliferation or migration of bovine corneal endothelial cells or primary mouse embryonic fibroblasts. In addition, we report the 3-D structure of mAng-4 at 2.02-Å resolution. The structure shows that the residues forming the putative B 1 , P 1 , and B 2 RNA-binding subsites occupy positions similar to their hAng counterparts. The B 1 subsite is obstructed by Glu115 and Ile118. The obstruction is stabilized by a novel salt bridge between the C-terminal carboxyl group and the side chain of Arg99. Through mutational studies, we identify residues critical to the angiogenic function of mAng-4. The effect of H12A and H112A mutations in the catalytic site indicates that ribonucleolytic activity is essential to angiogenesis. The consequences of a nearby E115A mutation are consistent with a significant role for Glu115 in the attenuation of enzymatic activity but also suggest that sufficient suppression of catalysis is necessary for angiogenesis. The effect of an R32A mutation in the putative nuclear localization sequence indicates that this residue is crucial for angiogenesis. In the putative cell-binding segment, the replacement of Lys59 with Asn (its counterpart at position 61 of hAng) does not abrogate enzymatic activity but abolishes angiogenic activity, the reason for which is unclear.

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Section: Resultsmentioning

confidence: 95%

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,

et al. 2007

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“…An important role in determining the low catalytic activity of angiogenins in comparison to RNase A has been ascribed to the obstruction of the B1 subsite that occurs in most angiogenins [16,28,29]. In these molecules a Glu/Gln residue on the C-terminal tail protrudes in the B1 subsite and forms two hydrogen bonds with the Thr involved in the pyrimidine base recognition.…”

Section: Discussionmentioning

confidence: 99%

“…Thus the topology of this fragment is substantially unchanged with respect to ZF-RNase-5, although the insertion of the two residues formally breaks the helix at the level of Ile30 (Figure 2 and supplemental Figure S3). In the case of ZF-RNase-3 (residues [23][24][25][26][27][28][29][30][31][32][33][34][35] [4] the first turn of the helix is highly distorted.…”

Section: Introductionmentioning

confidence: 99%

“…In ZF-RNase-5 this helix, which encompasses residues [24][25][26][27][28][29][30][31][32][33][34][35], has a first turn in a 3 10 conformation, and terminates with a turn in a π helix conformation with main chain hydrogen bonds Met31-Ile36 and Ser32-Lys35 and Lys35 in the Lα conformation. In the corresponding region (residues 23-36) of ZF-RNase-1 [4] the network of hydrogen bonds (Ile30-Ile37 and Gly31-Lys36) is spatially conserved.…”

Section: Introductionmentioning

confidence: 99%

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A new RNase sheds light on the RNase/angiogenin subfamily from zebrafish

Pizzo

Merlino

Turano

et al. 2010

Biochemical Journal

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Recently, extracellular RNases of the RNase A superfamily, with the characteristic CKxxNTF sequence signature, have been identified in fish. This has led to the recognition that these RNases are present in the whole vertebrate subphylum. In fact, they comprise the only enzyme family unique to vertebrates. Four RNases from zebrafish (Danio rerio) have been previously reported and have a very low RNase activity; some of these are endowed, like human angiogenin, with powerful angiogenic and bactericidal activities. In the present paper, we report the three-dimensional structure, the thermodynamic behaviour and the biological properties of a novel zebrafish RNase, ZF-RNase-5. The investigation of its structural and functional properties, extended to all other subfamily members, provides an inclusive description of the whole zebrafish RNase subfamily

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“…At the molecular level, crystal structures of ANG [human angiogenin ( Figure 1) (31,32), bovine angiogenin (33), and murine angiogenins -1 (34) and -4 (22)] have revealed the RNase A fold and conservation of the catalytic triad His13, Lys40, and His114 (ANG numbering). These structures, together with extensive functional and biochemical data, have provided a detailed understanding of the architecture of the ANG active site and the roles of the various residues involved in the binding and cleaving of RNA.…”

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confidence: 99%

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

et al. 2007

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Human angiogenin (ANG), the first member of the angiogenin family (from the pancreatic ribonuclease A superfamily) to be identified, is an angiogenic factor that induces neovascularization. It has received much attention due to its involvement in the growth of tumors and its elevated expression level in pancreatic and several other cancers. Recently the biological role of ANG has been shown to extend to the nervous system. Mutations in ANG have been linked with familial as well as sporadic forms of amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative disorder characterized by selective destruction of motor neurons. Furthermore, mouse angiogenin-1 has been shown to be expressed in the developing nervous system and during the neuronal differentiation of pluripotent stem cells. We have now characterized the seven variants of ANG reported in ALS patients with respect to the known biochemical properties of ANG and further studied the biological properties of three of these variants. Our results show that the ribonucleolytic activity of six of the seven ANG-ALS implicated variants is significantly reduced or lost and some variants also show altered thermal stability. We report a significant reduction in the cell proliferative and angiogenic activities of the three variants that we chose to investigate further. Our studies on the biochemical and structural features of these ANG variants now form the basis for further investigations to determine their role(s) in ALS.Amyotrophic lateral sclerosis (ALS) 1 is a fatal neurodegenerative disorder characterized by selective destruction of motor neurons (1). In the past decade, a small number of genes involved in the etiology of the disease have been identified (for a recent review see ref 2). The best studied of these is SOD1 (3), the gene for Cu/Zn superoxide dismutase. More than a hundred SOD1 mutations have now been linked with ALS, and motor neuron death from many of these mutations has been shown to result from a toxic gain of function rather than loss of dismutase activity. However, mutations in SOD1 account for only 1-2% of all cases of ALS and 20% of the familial cases. Some of the other proteins implicated in ALS are the vesicle-trafficking protein VAPB (4); ALSIN, a putative guanine nucleotide factor for GTPase (5); and senataxin (6). In addition, vascular endothelial growth factor (VEGF), an angiogenic factor that plays an important role in motor neuron survival, has been linked with ALS (7-10). However, the causes and molecular mechanisms underlying ALS are still largely unclear, and effective therapies do not appear to be imminent. Angiogenin (ANG), which encodes an angiogenic protein, was recently identified as a candidate susceptibility gene for ALS in the Irish and Scottish population by Greenway et al. (11). In a further study of over 2500 individuals from five independent populations from northern Europe and North America, Greenway et al. (12) found seven missense mutations (Figure 1) in 11 unrelated individuals with sporadic ALS and in f...

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Crystal structure of bovine angiogenin at 1.5-A resolution.

Cited by 49 publications

References 33 publications

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,

A new RNase sheds light on the RNase/angiogenin subfamily from zebrafish

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

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Crystal structure of bovine angiogenin at 1.5-A resolution.

Cited by 49 publications

References 33 publications

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein,

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein,

A new RNase sheds light on the RNase/angiogenin subfamily from zebrafish

Characterization of Human Angiogenin Variants Implicated in Amyotrophic Lateral Sclerosis

Contact Info

Product

Resources

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Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,

Biological and Structural Features of Murine Angiogenin-4, an Angiogenic Protein^,