7P2K

Solution NMR Structure of Arginine to Cysteine mutant of Arkadia RING domain.

Summary for 7P2K

• Entry DOI: 10.2210/pdb7p2k/pdb
• NMR Information: BMRB: 50985
• Descriptor: E3 ubiquitin-protein ligase Arkadia, ZINC ION (2 entities in total)
• Functional Keywords: arkadia, rnf111, e3 ubiquitin ligase, ring domain, arginine, tgf-b, ubch5b, ligase
• Biological source: Homo sapiens (Human)
• Total number of polymer chains: 1
• Total formula weight: 8036.80

Authors

Raptis, V.,Marousis, K.D.,Birkou, M.,Bentrop, D.,Episkopou, V.,Spyroulias, G.A. (deposition date: 2021-07-06, release date: 2022-03-23, Last modification date: 2024-06-19)

Primary citation

Birkou, M.,Raptis, V.,Marousis, K.D.,Tsevis, A.,Bourikas, K.,Bentrop, D.,Episkopou, V.,Spyroulias, G.A.
Impact of a Single Nucleotide Polymorphism on the 3D Protein Structure and Ubiquitination Activity of E3 Ubiquitin Ligase Arkadia.
Front Mol Biosci, 9:844129-844129, 2022

PubMed Abstract: Single nucleotide polymorphisms (SNPs) are genetic variations which can play a vital role in the study of human health. SNP studies are often used to identify point mutations that are associated with diseases. Arkadia (RNF111) is an E3 ubiquitin ligase that enhances transforming growth factor-beta (TGF-) signaling by targeting negative regulators for degradation. Dysregulation of the TGF- pathway is implicated in cancer because it exhibits tumor suppressive activity in normal cells while in tumor cells it promotes invasiveness and metastasis. Τhe SNP CGT > TGT generated an amino-acid (aa) substitution of Arginine 957 to Cysteine on the enzymatic RING domain of Arkadia. This was more prevalent in a tumor than in a normal tissue sample of a patient with colorectal cancer. This prompted us to investigate the effect of this mutation in the structure and activity of Arkadia RING. We used nuclear magnetic resonance (NMR) to analyze at an atomic-level the structural and dynamic properties of the R957C Arkadia RING domain, while ubiquitination and luciferase assays provided information about its enzymatic functionality. Our study showed that the R957C mutation changed the electrostatic properties of the RING domain however, without significant effects on the structure of its core region. However, the functional studies revealed that the R957C Arkadia exhibits significantly increased enzymatic activity supporting literature data that Arkadia within tumor cells promotes aggressive and metastatic behavior.

PubMed: 35281275
DOI: 10.3389/fmolb.2022.844129

Experimental method

SOLUTION NMR