The Fas-FADD Death Domain Complex Structure Reveals the Basis of DISC Assembly and Disease Mutations

Overview

Journal Nat Struct Mol Biol

Specialties Cell Biology
Molecular Biology

Date 2010 Oct 12

PMID 20935634

Citations 135

Authors

Liwei Wang

Jin Kuk Yang

Venkataraman Kabaleeswaran

Amanda J Rice

Anthony C Cruz

Ah Young Park

Qian Yin

Ermelinda Damko

Se Bok Jang

Stefan Raunser

Carol V Robinson

Richard M Siegel

Thomas Walz

Hao Wu

Affiliations

Soon will be listed here.

Abstract

The death-inducing signaling complex (DISC) formed by the death receptor Fas, the adaptor protein FADD and caspase-8 mediates the extrinsic apoptotic program. Mutations in Fas that disrupt the DISC cause autoimmune lymphoproliferative syndrome (ALPS). Here we show that the Fas-FADD death domain (DD) complex forms an asymmetric oligomeric structure composed of 5-7 Fas DD and 5 FADD DD, whose interfaces harbor ALPS-associated mutations. Structure-based mutations disrupt the Fas-FADD interaction in vitro and in living cells; the severity of a mutation correlates with the number of occurrences of a particular interaction in the structure. The highly oligomeric structure explains the requirement for hexameric or membrane-bound FasL in Fas signaling. It also predicts strong dominant negative effects from Fas mutations, which are confirmed by signaling assays. The structure optimally positions the FADD death effector domain (DED) to interact with the caspase-8 DED for caspase recruitment and higher-order aggregation.

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