2NA7

Transmembrane domain of human Fas/CD95 death receptor

Summary for 2NA7

• Entry DOI: 10.2210/pdb2na7/pdb
• Related: 2NA6
• NMR Information: BMRB: 25930
• Descriptor: Tumor necrosis factor receptor superfamily member 6 (1 entity in total)
• Functional Keywords: transmembrane helix trimer, transmembrane domain, proline-containing motif, apoptosis, structural genomics, psi-biology, membrane protein structures by solution nmr, mpsbynmr
• Biological source: Homo sapiens (human)
• Cellular location: Isoform 1: Cell membrane; Single-pass type I membrane protein. Isoform 2: Secreted. Isoform 3: Secreted. Isoform 4: Secreted. Isoform 5: Secreted. Isoform 6: Secreted: P25445
• Total number of polymer chains: 3
• Total formula weight: 9918.18

Authors

Fu, Q.,Chou, J.J.,Membrane Protein Structures by Solution NMR (MPSbyNMR) (deposition date: 2015-12-21, release date: 2016-01-27, Last modification date: 2024-05-15)

Primary citation

Fu, Q.,Fu, T.M.,Cruz, A.C.,Sengupta, P.,Thomas, S.K.,Wang, S.,Siegel, R.M.,Wu, H.,Chou, J.J.
Structural Basis and Functional Role of Intramembrane Trimerization of the Fas/CD95 Death Receptor.
Mol.Cell, 61:602-613, 2016

PubMed Abstract: Fas (CD95, Apo-1, or TNFRSF6) is a prototypical apoptosis-inducing death receptor in the tumor necrosis factor receptor (TNFR) superfamily. While the extracellular domains of TNFRs form trimeric complexes with their ligands and the intracellular domains engage in higher-order oligomerization, the role of the transmembrane (TM) domains is unknown. We determined the NMR structures of mouse and human Fas TM domains in bicelles that mimic lipid bilayers. Surprisingly, these domains use proline motifs to create optimal packing in homotrimer assembly distinct from classical trimeric coiled-coils in solution. Cancer-associated and structure-based mutations in Fas TM disrupt trimerization in vitro and reduce apoptosis induction in vivo, indicating the essential role of intramembrane trimerization in receptor activity. Our data suggest that the structures represent the signaling-active conformation of Fas TM, which appears to be different from the pre-ligand conformation. Analysis of other TNFR sequences suggests proline-containing sequences as common motifs for receptor TM trimerization.

PubMed: 26853147
DOI: 10.1016/j.molcel.2016.01.009

Experimental method

SOLUTION NMR