4b36

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Crystal Structure of Human Angiogenin with an Engineered Loop Exhibits Conformational Flexibility at the Functional Regions of the Molecule

Structural highlights

4b36 is a 2 chain structure with sequence from Homo sapiens. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
Method:X-ray diffraction, Resolution 1.76Å
Ligands:CL
Resources:FirstGlance, OCA, PDBe, RCSB, PDBsum, ProSAT

Disease

ANGI_HUMAN Defects in ANG are the cause of susceptibility to amyotrophic lateral sclerosis type 9 (ALS9) [MIM:611895. ALS is a degenerative disorder of motor neurons in the cortex, brain stem and spinal cord. ALS is characterized by muscular weakness and atrophy.[1] [2] [3] [4] [5] [6]

Function

ANGI_HUMAN May function as a tRNA-specific ribonuclease that abolishes protein synthesis by specifically hydrolyzing cellular tRNAs. Binds to actin on the surface of endothelial cells; once bound, angiogenin is endocytosed and translocated to the nucleus. Angiogenin induces vascularization of normal and malignant tissues. Angiogenic activity is regulated by interaction with RNH1 in vivo.[7] [8]

Publication Abstract from PubMed

Human angiogenin (ANG) is an angiogenic molecule and a ribonucleolytic enzyme with significant amino acid sequence identity to pancreatic RNase A, plays a critical role in the establishment and growth of tumours. An association between ANG and cancer has been observed in more than 25 clinical studies to date. In addition, ANG has now been shown to be implicated in Amyotrophic Lateral Sclerosis (ALS) and Parkinson's Disease (PD). Structural and biochemical studies so far have showed several distinguishing features of ANG molecule compared to RNase A and provided details of the putative cell binding site, active site, nuclear translocation sequence and the roles of residues in binding and cleaving RNA. A key finding elucidated from the structural study on ANG is the presence of a 'blocked' C-terminus (part of the active site apparatus) compared with RNase A. Here we report the crystal structure of ANG with an 'engineered-loop' from eosinophil derived neurotoxin (a homologue of ANG) which has resulted with local perturbations (conformational flexibility) at the cell binding site and at the C-terminus of the molecule. This experimental observation will now provide a new avenue to design compounds (potent inhibitors) through a structure guided drug design route.

Crystal structure of human angiogenin with an engineered loop exhibits conformational flexibility at the functional regions of the molecule.,Thiyagarajan N, Acharya KR FEBS Open Bio. 2012 Dec 26;3:65-70. doi: 10.1016/j.fob.2012.12.003. Print 2013. PMID:23772376[9]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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Citations
2 reviews cite this structure
Angiogenin and Copper Crossing in Wound Healing.
Cucci et al. (2021)
1 more
1 other articles
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See Also

References

  1. ↑ Wu D, Yu W, Kishikawa H, Folkerth RD, Iafrate AJ, Shen Y, Xin W, Sims K, Hu GF. Angiogenin loss-of-function mutations in amyotrophic lateral sclerosis. Ann Neurol. 2007 Dec;62(6):609-17. PMID:17886298 doi:10.1002/ana.21221
  2. ↑ Greenway MJ, Alexander MD, Ennis S, Traynor BJ, Corr B, Frost E, Green A, Hardiman O. A novel candidate region for ALS on chromosome 14q11.2. Neurology. 2004 Nov 23;63(10):1936-8. PMID:15557516
  3. ↑ Greenway MJ, Andersen PM, Russ C, Ennis S, Cashman S, Donaghy C, Patterson V, Swingler R, Kieran D, Prehn J, Morrison KE, Green A, Acharya KR, Brown RH Jr, Hardiman O. ANG mutations segregate with familial and 'sporadic' amyotrophic lateral sclerosis. Nat Genet. 2006 Apr;38(4):411-3. Epub 2006 Feb 26. PMID:16501576 doi:10.1038/ng1742
  4. ↑ Crabtree B, Thiyagarajan N, Prior SH, Wilson P, Iyer S, Ferns T, Shapiro R, Brew K, Subramanian V, Acharya KR. Characterization of human angiogenin variants implicated in amyotrophic lateral sclerosis. Biochemistry. 2007 Oct 23;46(42):11810-8. Epub 2007 Sep 27. PMID:17900154 doi:10.1021/bi701333h
  5. ↑ Gellera C, Colombrita C, Ticozzi N, Castellotti B, Bragato C, Ratti A, Taroni F, Silani V. Identification of new ANG gene mutations in a large cohort of Italian patients with amyotrophic lateral sclerosis. Neurogenetics. 2008 Feb;9(1):33-40. Epub 2007 Dec 18. PMID:18087731 doi:10.1007/s10048-007-0111-3
  6. ↑ Conforti FL, Sprovieri T, Mazzei R, Ungaro C, La Bella V, Tessitore A, Patitucci A, Magariello A, Gabriele AL, Tedeschi G, Simone IL, Majorana G, Valentino P, Condino F, Bono F, Monsurro MR, Muglia M, Quattrone A. A novel Angiogenin gene mutation in a sporadic patient with amyotrophic lateral sclerosis from southern Italy. Neuromuscul Disord. 2008 Jan;18(1):68-70. Epub 2007 Aug 20. PMID:17703939 doi:S0960-8966(07)00676-1
  7. ↑ Saxena SK, Rybak SM, Davey RT Jr, Youle RJ, Ackerman EJ. Angiogenin is a cytotoxic, tRNA-specific ribonuclease in the RNase A superfamily. J Biol Chem. 1992 Oct 25;267(30):21982-6. PMID:1400510
  8. ↑ Dickson KA, Kang DK, Kwon YS, Kim JC, Leland PA, Kim BM, Chang SI, Raines RT. Ribonuclease inhibitor regulates neovascularization by human angiogenin. Biochemistry. 2009 May 12;48(18):3804-6. doi: 10.1021/bi9005094. PMID:19354288 doi:10.1021/bi9005094
  9. ↑ Thiyagarajan N, Acharya KR. Crystal structure of human angiogenin with an engineered loop exhibits conformational flexibility at the functional regions of the molecule. FEBS Open Bio. 2012 Dec 26;3:65-70. doi: 10.1016/j.fob.2012.12.003. Print 2013. PMID:23772376 doi:10.1016/j.fob.2012.12.003

Contents


PDB ID 4b36

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