PDBsum entry 5v3p

Hydrolase,ligase

PDB id: 5v3p

Contents

Protein chains

316 a.a.

300 a.a.

308 a.a.

262 a.a.

Waters ×21

PDB id:

5v3p

Name:

Hydrolase,ligase

Title:

Human a20 otu domain (i325n) with acetamidylated c103

Structure:

Tumor necrosis factor alpha-induced protein 3. Chain: a, b, c, d, e, f. Fragment: otu domain (unp residues 1-366). Synonym: tnf alpha-induced protein 3,otu domain-containing protein 7c,putative DNA-binding protein a20,zinc finger protein a20. Engineered: yes. Mutation: yes. Other_details: c103 has been alkylated with iodoacetamide such that it has become an acetamidylated adduct (ycm).

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: tnfaip3, otud7c. Expressed in: escherichia coli. Expression_system_taxid: 469008.

Resolution:

2.50Å R-factor: 0.163 R-free: 0.200

Authors:

D.B.Langley,D.Christ,S.Grey

Key ref:

N.W.Zammit et al. (2019). Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity. Nat Immunol, 20, 1299-1310. PubMed id: 31534238 DOI: 10.1038/s41590-019-0492-0

Date:

07-Mar-17 Release date: 21-Mar-18

Supersedes:

5dod

Protein chains

P21580  (TNAP3_HUMAN) -  Tumor necrosis factor alpha-induced protein 3 from Homo sapiens

Seq: 790 a.a.

Struc: 316 a.a.*

Protein chains

P21580  (TNAP3_HUMAN) -  Tumor necrosis factor alpha-induced protein 3 from Homo sapiens

Seq: 790 a.a.

Struc: 300 a.a.*

Protein chain

P21580  (TNAP3_HUMAN) -  Tumor necrosis factor alpha-induced protein 3 from Homo sapiens

Seq: 790 a.a.

Struc: 308 a.a.*

Protein chain

P21580  (TNAP3_HUMAN) -  Tumor necrosis factor alpha-induced protein 3 from Homo sapiens

Seq: 790 a.a.

Struc: 262 a.a.*

* PDB and UniProt seqs differ at 8 residue positions (black crosses)

Enzyme reactions

• Enzyme class 1: Chains A, B, C, D, E, F: E.C.2.3.2.- - ?????
• Enzyme class 2: Chains A, B, C, D, E, F: E.C.3.4.19.12 - ubiquitinyl hydrolase 1.
• Reaction: Thiol-dependent hydrolysis of ester, thiolester, amide, peptide and isopeptide bonds formed by the C-terminal Gly of ubiquitin (a 76-residue protein attached to proteins as an intracellular targeting signal).

Note, where more than one E.C. class is given (as above), each may correspond to a different protein domain or, in the case of polyprotein precursors, to a different mature protein.

DOI no: 10.1038/s41590-019-0492-0

Nat Immunol 20:1299-1310 (2019)

PubMed id: 31534238

Denisovan, modern human and mouse TNFAIP3 alleles tune A20 phosphorylation and immunity.

N.W.Zammit, O.M.Siggs, P.E.Gray, K.Horikawa, D.B.Langley, S.N.Walters, S.R.Daley, C.Loetsch, J.Warren, J.Y.Yap, D.Cultrone, A.Russell, E.K.Malle, J.E.Villanueva, M.J.Cowley, V.Gayevskiy, M.E.Dinger, R.Brink, D.Zahra, G.Chaudhri, G.Karupiah, B.Whittle, C.Roots, E.Bertram, M.Yamada, Y.Jeelall, A.Enders, B.E.Clifton, P.D.Mabbitt, C.J.Jackson, S.R.Watson, C.N.Jenne, L.L.Lanier, T.Wiltshire, M.H.Spitzer, G.P.Nolan, F.Schmitz, A.Aderem, B.T.Porebski, A.M.Buckle, D.W.Abbott, J.B.Ziegler, M.E.Craig, P.Benitez-Aguirre, J.Teo, S.G.Tangye, C.King, M.Wong, M.P.Cox, W.Phung, J.Tang, W.Sandoval, I.E.Wertz, D.Christ, C.C.Goodnow, S.T.Grey.

ABSTRACT

Resisting and tolerating microbes are alternative strategies to survive infection, but little is known about the evolutionary mechanisms controlling this balance. Here genomic analyses of anatomically modern humans, extinct Denisovan hominins and mice revealed a TNFAIP3 allelic series with alterations in the encoded immune response inhibitor A20. Each TNFAIP3 allele encoded substitutions at non-catalytic residues of the ubiquitin protease OTU domain that diminished IκB kinase-dependent phosphorylation and activation of A20. Two TNFAIP3 alleles encoding A20 proteins with partial phosphorylation deficits seemed to be beneficial by increasing immunity without causing spontaneous inflammatory disease: A20 T108A;I207L, originating in Denisovans and introgressed in modern humans throughout Oceania, and A20 I325N, from an N-ethyl-N-nitrosourea (ENU)-mutagenized mouse strain. By contrast, a rare human TNFAIP3 allele encoding an A20 protein with 95% loss of phosphorylation, C243Y, caused spontaneous inflammatory disease in humans and mice. Analysis of the partial-phosphorylation A20 I325N allele in mice revealed diminished tolerance of bacterial lipopolysaccharide and poxvirus inoculation as tradeoffs for enhanced immunity.