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2L8R

Solution structure of human protein C6orf130 in complex with ADP-ribose

Summary for 2L8R
Entry DOI10.2210/pdb2l8r/pdb
Related2JYC 2LGR
NMR InformationBMRB: 17421
DescriptorUncharacterized protein C6orf130, ADENOSINE-5-DIPHOSPHORIBOSE (2 entities in total)
Functional Keywordsmacro domain, structural genomics, protein structure initiative, psi-2, center for eukaryotic structural genomics, cesg, deacylase, hydrolase
Biological sourceHomo sapiens (human)
Total number of polymer chains1
Total formula weight17463.82
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 citationPeterson, 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: 21849506
DOI: 10.1074/jbc.M111.276238
PDB entries with the same primary citation
Experimental method
SOLUTION NMR
Structure validation

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