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IAPs, RINGs and ubiquitylation

Key Points

  • IAPs are inhibitors of apoptosis proteins, which contain baculovirus inhibitor of apoptosis repeat (BIR) and RING domains. IAPs can inhibit caspases directly, thereby preventing apoptosis, and can be antagonized by the binding of IAP antagonists to their BIR domains.

  • Ubiquitylation of a target protein can give rise to many diverse outcomes, not just proteasomal degradation.

  • The RING domain is important in the ability of IAPs to inhibit apoptosis. RING domains can function as E3 ligases by binding to E2 ubiquitin-conjugating enzymes (UBCs) and recruiting E2s to a substrate. Diap1 (Drosophila melanogaster IAP1) has been shown to interact genetically with the E2 UBCD1 and the E2-like morgue.

  • IAPs have been shown to be able to catalyse the ubiquitylation of a large number of IAP-interacting proteins in vitro, including caspases, IAP antagonists, tumour necrosis factor (TNF) receptor-associated factors (TRAFs) and MURR1. But the relevance of many of these interactions in vivo is still unknown.

  • The IAP half-life is regulated by the RING domain and, in some cases, the half-life can be regulated by IAP-binding proteins.

Abstract

The inhibitor of apoptosis (IAP) proteins all contain one or more baculoviral IAP repeat motifs, through which they interact with various other proteins. Many IAPs also have another zinc-binding motif, the RING domain, which can recruit E2 ubiquitin-conjugating enzymes and catalyse the transfer of ubiquitin onto target proteins. The number of targets of IAP-mediated ubiquitylation is increasing and recent results indicate that outcomes following ubiquitylation are tantalizingly complex. As well as regulating other proteins, the IAPs themselves are controlled by ubiquitin-mediated degradation.

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Figure 1: A selection of inhibitor of apoptosis (IAP) proteins.
Figure 2: RING-containing E3 ligases often have a conserved multisubunit composition.
Figure 3: Inhibitor of apoptosis (IAP) interactions.
Figure 4: An abundance of inhibitor of apoptosis (IAP) binding and ubiquitylation.
Figure 5: Ubiquitylation of components of tumour necrosis factor (TNF) signalling complex.

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DATABASES

Swiss-Prot

TRAF2

XIAP

FlyBase

DIAP1

DRONC

Interpro

RING

FURTHER INFORMATION

RING-finger description

List of BIR-containing proteins

Table of E3 ubiquitin ligases

Database of apoptosis related subjects

Protein Data Bank

Glossary

BACULOVIRUS INHIBITOR OF APOPTOSIS REPEAT

(BIR). Cysteine-based motif of 65 amino acids. Inhibitors of apoptosis contain several BIR domains.

E2 UBIQUITIN-CONJUGATING ENZYME

An enzyme that accepts ubiquitin or a ubiquitin-like protein from an E1 and transfers it to the substrate, mostly using an E3 enzyme.

26S PROTEASOME

The main chambered protease of eukaryotes. Named for its approximate sedimentation coefficient, it is assembled from proteolytic (20S) and regulatory (19S) complexes.

E3 UBIQUITIN LIGASE

The third enzyme in a series — the first two are designated E1 and E2 — that is responsible for ubiquitylation of target proteins. E3 enzymes provide platforms for binding E2 enzymes and specific substrates, thereby coordinating ubiquitylation of the selected substrates.

RING FINGER

A protein-sequence motif corresponding to a particular folded protein domain that binds Zn2+ through a four-point arrangement of cysteine and histidine amino acids. In the E3 ubiquitin ligases, this domain seems to be responsible for binding the E2 ubiquitin-conjugating enzymes.

CASPASE RECRUITMENT DOMAIN

A conserved domain that is found in cIAP1 and cIAP2. The function of the domain in these molecules is currently unknown.

CULLINS

A family of proteins that are characterized by the presence of a distinct globular C-terminal domain (cullin-homology domain) and a series of N-terminal repeats of a five-helix bundle (cullin repeats).

F-BOX PROTEIN

(FBP). A component of the machinery for the ubiquitin-dependent degradation of proteins. FBPs recognize specific substrates and, with the help of other subunits of the E3 ubiquitin ligase, deliver them to the E2 ubiquitin-conjugating enzyme.

SOCS BOX

Suppressor of cytokine signalling box first identified in an inhibitor of Jak-family kinases.

ZYMOGEN

A proteolytically inactive precursor of a protease. Most of these proteases contain a prodomain at the N terminus, which keeps the corresponding enzyme inactive. The prodomain is removed by endoproteolysis. This can be mediated by other proteases (so zymogens and their activating proteases are often members of a proteolytic cascade), or by autoproteolysis.

HYPOMORPHIC

A mutation that reduces, but does not completely eliminate, the function of a gene.

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Vaux, D., Silke, J. IAPs, RINGs and ubiquitylation. Nat Rev Mol Cell Biol 6, 287–297 (2005). https://doi.org/10.1038/nrm1621

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