The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
TRIM7 C-terminal Q degrons
Functional site description:
C-terminal degrons (C-degrons, also known as destabilizing C-terminal ends, DesCEnds) are short amino acid sequences located at the C-terminus of proteins that play a crucial role in regulating protein stability and degradation. These degrons are recognized by specific E3 ubiquitin ligases, such as the TRIM7 E3 ligase, which target multiple substrates with unrelated biological functions for ubiquitination and subsequent proteasomal degradation. TRIM7 is a vertebrate-specific ubiquitin ligase potentially involved in innate immunity as well as other cellular processes. It is capable of recognizing either RNA virus proteins cleaved by a glutamine-directed viral protease as well as a set of cellular substrates possessing an appropriate, disordered C-terminus, matching with the substrate preference of TRIM7. The B30.2/SPRY domain of TRIM7 interacts with proteins containing a C-terminus ending in a helix-ΦQ motif (Luptak,2022). Here Φ must be hydrophobic, usually either Leu or Phe.
ELM Description:
TRIM7 degrons bind to SPRY (also known as B30.2 or PRY-SPRY) domains through their C-terminal glutamine amino acid preceded with a hydrophobic residue (phenylalanine or leucine), usually in a helical conformation (Ru,2022 and Luptak,2022). This ‘helix-ΦQ’ degron motif is recognized by TRIM7.
TRIM7 forms a positively charged binding pocket to engage the "U"-shaped Q$ C-degron. The four C-terminal residues of a substrate play an important role in C-degron recognition, with C-terminal glutamine as the principal determinant (Ru,2022). These preceding residues typically form an α-helix upon binding, although slightly different conformations where the helix is overwound have also been observed with certain substrates.
The positively charged TRIM7 SPRY domain pocket includes an arginine residue (R385) to form a bidentate salt bridge with the carboxylic acid at the motif C-terminus while also forming an H-bond with the key substrate glutamine side chain. In addition, hydrophobic pockets are available for the preceding residues. TRIM7 residues N383, R385, G408, W409, L423, F426, Q436, L437, S499 participate in the binding. The -4 residue (with the C-terminal Gln being residue 0) is typically small, to fit a matching, narrow pocket on the SPRY domain. However, the non-α-helical motifs contact the same site using their -3 residue, suggesting a large plasticity in the surface binding beyond the last 2 residues (7OW2, 7OVX, 8A5L, 8A5M, 7Y3A, 7Y3B, 7Y3C).
Pattern: [^P][^P][FL]Q$
Pattern Probability: 0.0000076
Present in taxons: Vertebrata Viruses
Interaction Domain:
SPRY domain (IPR003877) The SPRY domain is named from SPla and the RYanodine Receptor and it is found in many eukaryotic proteins with a wide range of functions (Stochiometry: 1 : 1)
o See 6 Instances for DEG_Cend_TRIM7_1
o Abstract
The genome can be subject to various types of damage, such as germline mutations, replication errors and more. The mRNA molecules can also be mis-processed or translated erroneously. In addition, protein molecules can suffer chemical damage (e.g. hydrolysis) as they age. Protein quality control is a vital cellular process that ensures the proper folding, assembly, and function of proteins. It involves various surveillance mechanisms that detect misfolded or damaged proteins and either facilitate their refolding or target them for degradation via protein degradation pathways such as the ubiquitin-proteasome system, thereby maintaining cellular homeostasis (Yeh,2021).
C-degron pathways have been implicated in various biological processes, including protein quality surveillance, cell cycle regulation, antiviral defence, and signal transduction. Dysregulation of C-degron pathways can lead to the accumulation of abnormal or misfolded proteins, contributing to the development of human diseases such as neurodegenerative disorders (Chen,2021).
C-terminal degrons can be present in full length proteins internally, in which case they must be revealed by proteolytic cleavage. On the other hand, they can be natively present at the C-termini of other proteins or even introduced by premature translation termination.
The TRIM7 ubiquitin ligase recognizes proteins ending in the phenylalanine-glutamine or leucine-glutamine sequence. Experimentally determined structures show that the peptides are bound to the B30.2/SPRY domain in a helical conformation. Similar to other members of the TRIM ubiquitin ligase family, TRIM7 is also considered to play a role in innate immunity by acting as an antiviral effector. Although, only a few known full length cellular substrates ending in the FQ or LQ sequence have been identified (most notably, glycogenin and E3 ligase RNF187), such sites are frequently observed in the proteins of RNA viruses (Ru,2022). Many RNA viruses encode long polyproteins that are cleaved to individual structural and non-structural proteins by glutamine-directed proteases, generating potential TRIM7 substrates. Hence TRIM7 can effectively restrict viral replication by targeting at least a subset of the viral polyprotein cleavage products to ubiquitin-dependent degradation. However, TRIM7′s restricted tissue expression (at least in humans) and lack of immune regulation suggests that viral restriction may or may not be its physiological function (Q9C029, Luptak,2022). For example, in striated muscle, it might be involved in regulating glycogen formation by targeting glycogenin (Skurat,2002).
TRIM7 is mostly involved in the K48-linked polyubiquitylation (triggering proteasome-dependent degradation) of most of its substrates, except for RNF187 (also known as RACO-1). On this latter substrate (which is also an ubiquitin ligase itself), TRIM7 aids the assembly of immune-activating, K63-linked polyubiquitin chains (Chakraborty,2015).
While many RNA virus polyprotein cleavage sites (typically cleaved after glutamine) were found to be potential TRIM7 substrates, these targets are mostly featured in their uncleaved precursor form in the UniProt database. This precludes automatic detection of putative viral substrate proteins, as proteolytic sites need to be mapped and verified first.
RNA virus protein entries in UniProt are for the full length polyprotein. Therefore the C-degrons for the cleaved products shown in ELM do not correspond to the actual C-terminus of the UniProt sequence. Additional instances which are missing from the instance table are Coxsackievirus B3 Genome polyprotein (P03313, 1428-1429 (7Y3A)), SARS2 Replicase polyprotein (P0DTD1, 3568-3569 (7x6y); 4139-4140 (7x70), and Murine norovirus 1 Genome polyprotein (Q80J95, 704-705 (8a8x).
o 4 selected references:

o 8 GO-Terms:

o 6 Instances for DEG_Cend_TRIM7_1
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
P03313 Genome polyprotein
1426 1429 MFREYNHRHSVGTTLEALFQ TP 6 Coxsackievirus B3 (strain Nancy)
B9VUU3 Genome polyprotein
1437 1440 LIREYSNRSAIGNTIEALFQ TP 9 Enterovirus A71
Q80J95 Polyprotein
1174 1177 GNTVIAATHGEPTLEALEFQ TP 9 Murine norovirus 1
P0DTD1 rep
5321 5324 SRYWEPEFYEAMYTPHTVLQ TP 6 Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
P46976 GYG1
347 350 DYMGADSFDNIKRKLDTYLQ TP 15 Homo sapiens (Human)
Q5TA31 RNF187
232 235 QAVSELEKKHRNLGLSMLLQ TP 16 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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