Genetics of Apoptosis

4.

Functional domains in apoptosis proteins

Kay Hofmann

1.

Introduction

The analysis of the modular structure of apoptotic signaling proteins has contributed
on several levels to our current understanding of the signal transduction networks
involved. The main purpose of this chapter is to discuss the functional domain types
frequently occurring in proteins that are encoded by apoptosis genes. Besides the
functional aspects of those domains, the structure of representative members will be
discussed briefly, whenever available.
The first paragraph starts by introducing the domain concept, explaining the
relationship between ‘structural domains’ and ‘functional domains’. The methods
being used to identify homology domains and to detect their occurrence in protein
sequences are briefly discussed. While functional domains are present in all major
signaling pathways, they are particularly abundant in apoptotic signaling, owing to
the ‘multiple-adapter’ architecture of the pathways involved. The following
paragraphs review the most commonly found domain types and discuss what is known
about their modus operandi. The most upstream event of apoptosis signaling is the
interaction between a death-inducing ligand and its receptor. This interaction is
mediated by two particular domain types, one (TNH for TNF homology) found in
the ligand, and the other one (TNFR-CRD for TNF receptor cysteine-rich domain)
in the respective receptors. The death receptors relay the apoptosis signal by their
cytoplasmic region containing another domain type, the ‘death domain’ (DD). The
next steps involve a number of adapter proteins harboring interaction domains of the
six-helix bundle superfamily, namely, death domains (DD), death effector domains
(DED), caspase recruitment domains (CARD), and pyrin domains (PYD). Several
of these adapter proteins branch the signaling pathway towards nonapoptotic
outcomes, including NF-κB activation. The presence of TRAF domains or Toll/IL–
1R domain (TIR) is a hallmark of those proteins. Eventually, the recruitment of the
death adapter proteins leads to the activation of caspases, a class of proteases
specifically cleaving a number of substrates, including other caspases. A prominent
class of physiologic caspase inhibitors containing the ‘BIR’ domain adds another level
of regulation.