PDBsum entry 4mxw

Cytokine/immune system

PDB id: 4mxw

Contents

Protein chains

79 a.a.

134 a.a.

131 a.a.

134 a.a.

149 a.a.

212 a.a.

211 a.a.

PDB id:

4mxw

Name:

Cytokine/immune system

Title:

Structure of heterotrimeric lymphotoxin lta1b2 bound to lymphotoxin beta receptor ltbr and anti-lta fab

Structure:

Tumor necrosis factor receptor superfamily member 3. Chain: s, r. Synonym: lymphotoxin-beta receptor, tumor necrosis factor c receptor, tumor necrosis factor receptor 2-related protein, tumor necrosis factor receptor type iii, tnf-riii, tnfr-iii. Engineered: yes. Lymphotoxin-alpha. Chain: x, a. Synonym: lt-alpha, tnf-beta, tumor necrosis factor ligand superfamily

Source:

Homo sapiens. Human. Organism_taxid: 9606. Gene: ltbr, d12s370, tnfcr, tnfr3, tnfrsf3. Expressed in: trichoplusia ni. Expression_system_taxid: 7111. Gene: lta, tnfb, tnfsf1. Gene: ltb, tnfc, tnfsf3. Expressed in: cricetulus griseus.

Resolution:

3.60Å R-factor: 0.234 R-free: 0.296

Authors:

J.Sudhamsu,J.P.Yin,S.G.Hymowitz

Key ref:

J.Sudhamsu et al. (2013). Dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction. Proc Natl Acad Sci U S A, 110, 19896-19901. PubMed id: 24248355 DOI: 10.1073/pnas.1310838110

Date:

26-Sep-13 Release date: 13-Nov-13

Protein chain

P36941  (TNR3_HUMAN) -  Tumor necrosis factor receptor superfamily member 3 from Homo sapiens

Seq: 435 a.a.

Struc: 79 a.a.

Protein chains

P01374  (TNFB_HUMAN) -  Lymphotoxin-alpha from Homo sapiens

Seq: 205 a.a.

Struc: 134 a.a.*

Protein chains

Q06643  (TNFC_HUMAN) -  Lymphotoxin-beta from Homo sapiens

Seq: 244 a.a.

Struc: 131 a.a.

Protein chains

Q06643  (TNFC_HUMAN) -  Lymphotoxin-beta from Homo sapiens

Seq: 244 a.a.

Struc: 134 a.a.

Protein chain

P36941  (TNR3_HUMAN) -  Tumor necrosis factor receptor superfamily member 3 from Homo sapiens

Seq: 435 a.a.

Struc: 149 a.a.

Protein chains

No UniProt id for this chain

Struc: 212 a.a.

Protein chains

No UniProt id for this chain

Struc: 211 a.a.

* PDB and UniProt seqs differ at 1 residue position (black cross)

DOI no: 10.1073/pnas.1310838110

Proc Natl Acad Sci U S A 110:19896-19901 (2013)

PubMed id: 24248355

Dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction.

J.Sudhamsu, J.Yin, E.Y.Chiang, M.A.Starovasnik, J.L.Grogan, S.G.Hymowitz.

ABSTRACT

Homotrimeric TNF superfamily ligands signal by inducing trimers of their cognate receptors. As a biologically active heterotrimer, Lymphotoxin(LT)α1β2 is unique in the TNF superfamily. How the three unique potential receptor-binding interfaces in LTα1β2 trigger signaling via LTβ Receptor (LTβR) resulting in lymphoid organogenesis and propagation of inflammatory signals is poorly understood. Here we show that LTα1β2 possesses two binding sites for LTβR with distinct affinities and that dimerization of LTβR by LTα1β2 is necessary and sufficient for signal transduction. The crystal structure of a complex formed by LTα1β2, LTβR, and the fab fragment of an antibody that blocks LTβR activation reveals the lower affinity receptor-binding site. Mutations targeting each potential receptor-binding site in an engineered single-chain variant of LTα1β2 reveal the high-affinity site. NF-κB reporter assays further validate that disruption of receptor interactions at either site is sufficient to prevent signaling via LTβR.