TRAF proteiini on trimerisoituna fnktionaalinen.

https://www.sciencedirect.com/topics/biochemistry-genetics-and-molecular-biology/tnf-receptor-associated-factor 

Perustietoja:

 

ian Yin, ... Hao Wu, in Handbook of Cell Signaling (Second Edition), 2010

Regulation of TRAF Signaling

TRAF signaling is tightly regulated by many mechanisms; in particular, oligomerization and ubiquitination. These regulatory mechanisms ensure that TRAFs are activated upon ligand stimulation and turned off at the appropriate times. Oligomerization appears to be the common theme of TRAF6 activation in all known signaling pathways: oligomerization by TNFRs, by TIR signaling complexes, and by the CBM complex. The C-terminal TRAF domain mediates its trimerization. 

Forced dimerization by fused dimerizing domain also activates TRAF6 [47]. A cytosolic TRAF-interacting protein known as TIFA, with a forkhead-associated (FHA) domain, can enhance TRAF6 oligomerization and activation [48].

Several de-ubiquitinating and ubiquitinating enzymes, such as A20 and CYLD, have been shown to provide feedback inhibition of TRAF-mediated NFκB activation. A20 was originally characterized as an early response gene to TNF stimulation [49], and possesses dual ubiquitin editing functions [50]. While the N-terminal domain of A20 is a de-ubiquitinating enzyme (DUB) for Lys63-linked polyubiquitination of signaling mediators such as TRAF6 and RIP, its C-terminal domain is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates [50–54]. CYLD is Lys63-specific de-ubiquitinating enzyme, whose mutations are the underlying causes of familial cylindromatosis, with predisposition to tumors of skin appendages called cylindromas [44–46, 54, 55].

 

2. lähde 

 

1QSC

CRYSTAL STRUCTURE OF THE TRAF DOMAIN OF TRAF2 IN A COMPLEX WITH A PEPTIDE FROM THE CD40 RECEPTOR

• DOI: 10.2210/pdb1QSC/pdb

• Classification: SIGNALING PROTEIN
• Organism(s): Homo sapiens
• Expression System: Spodoptera frugiperda
• Mutation(s): No 

 

3.lähde 

Qian Yin, ... Hao Wu, in Handbook of Cell Signaling (Second Edition), 2010

Regulation of TRAF Signaling

TRAF signaling is tightly regulated by many mechanisms; in particular, oligomerization and ubiquitination. These regulatory mechanisms ensure that TRAFs are activated upon ligand stimulation and turned off at the appropriate times. Oligomerization appears to be the common theme of TRAF6 activation in all known signaling pathways: oligomerization by TNFRs, by TIR signaling complexes, and by the CBM complex. The C-terminal TRAF domain mediates its trimerization. Forced dimerization by fused dimerizing domain also activates TRAF6 [47]. A cytosolic TRAF-interacting protein known as TIFA, with a forkhead-associated (FHA) domain, can enhance TRAF6 oligomerization and activation [48].

Several de-ubiquitinating and ubiquitinating enzymes, such as A20 and CYLD, have been shown to provide feedback inhibition of TRAF-mediated NFκB activation. A20 was originally characterized as an early response gene to TNF stimulation [49], and possesses dual ubiquitin editing functions [50]. While the N-terminal domain of A20 is a de-ubiquitinating enzyme (DUB) for Lys63-linked polyubiquitination of signaling mediators such as TRAF6 and RIP, its C-terminal domain is a ubiquitin ligase (E3) for Lys48-linked degradative polyubiquitination of the same substrates [50–54]. CYLD is Lys63-specific de-ubiquitinating enzyme, whose mutations are the underlying causes of familial cylindromatosis, with predisposition to tumors of skin appendages called cylindromas [44–46, 54, 55].

4. . lähde:

SARS-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the MAVS/TRAF3/TRAF6 signalosome

• August 2014
• The Journal of Immunology 193(6)

DOI:10.4049/jimmunol.1303196

• Source
• PubMed

 

5. lähde. Sars-s proteiini  muodostaa trimerisoidun funktionaalisen kokoomuksen: 

Here, we present cryo-EM structures of SARS-CoV-2 S trimer in a tightly closed state with packed FP may represent the ground prefusion state, and the S trimer in complex with the receptor ACE2 (termed SARS-CoV-2 S-ACE2) at 2.7- and 3.8-Å resolution, respectively, in addition to an S trimer structure in the unliganded open state. The tightly closed ground prefusion state with originally dominant population may indicate a conformational masking mechanism of immune evasion for SARS-CoV-2 spike. Our data suggested that there is one RBD in the up conformation and is trapped by ACE2 in the S-ACE2 complex. Notably, ACE2 can greatly shift the conformational landscape of S trimer, and the associated ACE2-RBD exhibits continuous swing motions in the context of the S trimer, resulting in conformational dynamics in S1 subunits. We also provided structural basis of the enhanced infectivity induced by spike D614G mutation and demonstrated the RBM T470-T478 loop and residue Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings reveal the mechanism of ACE2-induced conformational transitions of S trimer from the ground prefusion state toward the postfusion state, enhance our understanding of SARS-CoV-2 infection, and provide important information for the design and optimization of anti–SARS-CoV-2 vaccines and therapeutics.

RESULTS

A tightly closed state of SARS-CoV-2 S trimer

Prefusion stabilized ectodomain trimer of SARS-CoV-2 S glycoprotein was produced from human embryonic kidney (HEK) 293F cells using the strategy also adopted in other studies (fig. S1, A to D) (2, 7, 8, 23–28), and was subjected to cryo-EM single-particle analysis (fig. S2, A to B). Our initial reconstruction suggested a preferred orientation problem associated with the S trimer (highly preferred “side” orientation but lacking tilted top views; fig. S2C), which is also the case for the influenza hemagglutinin trimer (but highly preferred “top” orientation) (29). To overcome this problem, we adopted the recently developed tilt stage strategy in data collection with additional data collected at 30° and 40° tilt angles (29). This allowed us to obtain a cryo-EM structure of SARS-CoV-2 S trimer in a closed state at 2.7-Å resolution (with imposed C3 symmetry, termed S-closed) (Fig. 1A, figs. S2 and S3, and table S1). After overcoming the preferred orientation problem, our S-closed map very well resolved the peripheral edge of the NTD domain and the RBM S469-C488 loop (Fig. 1, A to D), which was less well resolved in the similar stabilized ectodomain trimer structures (7, 8). This enabled us to build an atomic model of the SARS-CoV-2 S trimer (Fig. 1B; fig. S2, F and G; and movie S1).

Here, we present cryo-EM structures of SARS-CoV-2 S trimer in a tightly closed state with packed FP may represent the ground prefusion state, and the S trimer in complex with the receptor ACE2 (termed SARS-CoV-2 S-ACE2) at 2.7- and 3.8-Å resolution, respectively, in addition to an S trimer structure in the unliganded open state. The tightly closed ground prefusion state with originally dominant population may indicate a conformational masking mechanism of immune evasion for SARS-CoV-2 spike. Our data suggested that there is one RBD in the up conformation and is trapped by ACE2 in the S-ACE2 complex. Notably, ACE2 can greatly shift the conformational landscape of S trimer, and the associated ACE2-RBD exhibits continuous swing motions in the context of the S trimer, resulting in conformational dynamics in S1 subunits. We also provided structural basis of the enhanced infectivity induced by spike D614G mutation and demonstrated the RBM T470-T478 loop and residue Y505 as viral determinants for specific recognition of SARS-CoV-2 RBD by ACE2. Our findings reveal the mechanism of ACE2-induced conformational transitions of S trimer from the ground prefusion state toward the postfusion state, enhance our understanding of SARS-CoV-2 infection, and provide important information for the design and optimization of anti–SARS-CoV-2 vaccines and therapeutics.