2L8R
Solution structure of human protein C6orf130 in complex with ADP-ribose
Summary for 2L8R
Entry DOI | 10.2210/pdb2l8r/pdb |
Related | 2JYC 2LGR |
NMR Information | BMRB: 17421 |
Descriptor | Uncharacterized protein C6orf130, ADENOSINE-5-DIPHOSPHORIBOSE (2 entities in total) |
Functional Keywords | macro domain, structural genomics, protein structure initiative, psi-2, center for eukaryotic structural genomics, cesg, deacylase, hydrolase |
Biological source | Homo sapiens (human) |
Total number of polymer chains | 1 |
Total formula weight | 17463.82 |
Authors | Lytle, B.L.,Peterson, F.C.,Volkman, B.F.,Center for Eukaryotic Structural Genomics (CESG) (deposition date: 2011-01-22, release date: 2011-02-23, Last modification date: 2024-05-01) |
Primary citation | Peterson, F.C.,Chen, D.,Lytle, B.L.,Rossi, M.N.,Ahel, I.,Denu, J.M.,Volkman, B.F. Orphan Macrodomain Protein (Human C6orf130) Is an O-Acyl-ADP-ribose Deacylase: SOLUTION STRUCTURE AND CATALYTIC PROPERTIES. J.Biol.Chem., 286:35955-35965, 2011 Cited by PubMed Abstract: Post-translational modification of proteins/histones by lysine acylation has profound effects on the physiological function of modified proteins. Deacylation by NAD(+)-dependent sirtuin reactions yields as a product O-acyl-ADP-ribose, which has been implicated as a signaling molecule in modulating cellular processes. Macrodomain-containing proteins are reported to bind NAD(+)-derived metabolites. Here, we describe the structure and function of an orphan macrodomain protein, human C6orf130. This unique 17-kDa protein is a stand-alone macrodomain protein that occupies a distinct branch in the phylogenic tree. We demonstrate that C6orf130 catalyzes the efficient deacylation of O-acetyl-ADP-ribose, O-propionyl-ADP-ribose, and O-butyryl-ADP-ribose to produce ADP-ribose (ADPr) and acetate, propionate, and butyrate, respectively. Using NMR spectroscopy, we solved the structure of C6orf130 in the presence and absence of ADPr. The structures showed a canonical fold with a deep ligand (ADPr)-binding cleft. Structural comparisons of apo-C6orf130 and the ADPr-C6orf130 complex revealed fluctuations of the β(5)-α(4) loop that covers the bound ADPr, suggesting that the β(5)-α(4) loop functions as a gate to sequester substrate and offer flexibility to accommodate alternative substrates. The ADPr-C6orf130 complex identified amino acid residues involved in substrate binding and suggested residues that function in catalysis. Site-specific mutagenesis and steady-state kinetic analyses revealed two critical catalytic residues, Ser-35 and Asp-125. We propose a catalytic mechanism for deacylation of O-acyl-ADP-ribose by C6orf130 and discuss the biological implications in the context of reversible protein acylation at lysine residues. PubMed: 21849506DOI: 10.1074/jbc.M111.276238 PDB entries with the same primary citation |
Experimental method | SOLUTION NMR |
Structure validation
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