The Eukaryotic Linear Motif resource for
Functional Sites in Proteins
Functional site class:
FEM1ABC C-terminal Arg degrons
Functional site description:
C-degrons play critical roles in targeting the receptor proteins of several cullin-RING E3 ligase complexes (CRLs) to initiate protein degradation. FEM1 proteins, including FEM1A/B/C, act as the receptors to specifically recognize C degrons ending with arginine (Arg/C-degron) to enable CRL2-mediated proteasomal turnover

Cul2 ligase complexes, including Cul2FEM1A, Cul2FEM1B, and Cul2FEM1C, are responsible for targeting substrates with arginine as their C-terminal residue (Koren,2018; Lin,2018). Meanwhile some of the known substrates have native C-termini ending in Arg, others are generated through proteolysis.
ELMs with same func. site: DEG_Cend_FEM1AC_1  DEG_Cend_FEM1B_2 
ELM Description:
Cul2 ligase complexes, including Cul2FEM1A, Cul2FEM1B, and Cul2FEM1C, are responsible for targeting substrates with arginine as their C-terminal residue (Koren,2018; Lin,2018). The specificities of FEM1A, FEM1B and FEM1C overlap considerably, but they do have marked preferences in their substrates (Chen,2021). FEM1A and FEM1C prefer charged, while FEM1B hydrophobic residues preceding the carboxy-terminal Arg residue (Timms,2020). The degron binding pocket for these substrates involves ankyrin repeats within the FEM1-family substrate adaptors. FEM1A/B/C degrons bind to ankyrin repeats via the C-terminal arginine. In the case of FEM1B binding to CD5R1_HUMAN (7cng), the C-terminal Arg binds with FEM1B via cation-π and hydrogen bonds to a negatively charged pocket. Leu at position -3 interacts with Tyr163 and Phe193. Flanking region also interacts with FEM1B: Gly at position -4 binds to Asn151 though hydrogen binding and to Cys186 and His218 via van de Waals interactions; Leu at position -5/-7 might form hydrogen bonds with Tyr153, Cys186 and His218; Arg at position -8 forms salt bridge with Glu196 (Chen,2021). Highly similar interactions occur when FEM1B binds to SMCR8_HUMAN isoform 2 (7el6): The C-terminal arginine binds to Asp82 and Asp131, while cation- π interactions occur with Phe81 and Phe130 and hydrogen bonds form with Trp93 and Ser122. In addition to binding Tyr163 and Phe193, Leu -3 also binds to Ile160. Gly at position -4 forms van der Waals interaction with Tyr153 and Trp at -8 position interacts with His185 (Zhao,2021). The degron size recognized by FEM1 proteins may be notably larger than other C-degron pathways, as evident from experiments where transplanting the last 25 amino acids was necessary to destabilize a heterologous protein (Lin,2018).
Pattern: .L.R$
Pattern Probability: 0.0000083
Present in taxon: Metazoa
Interaction Domain:
Ankyrin repeat (IPR002110) The ankyrin repeat is one of the most common protein-protein interaction motifs in nature (Stochiometry: 1 : 1)
o See 2 Instances for DEG_Cend_FEM1B_2
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-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, DCAF12, FEM1B and KLHDC2 E3 ligases, which target the protein for ubiquitination and subsequent proteasomal degradation.

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 activated 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.

Within the cullin2-RING E3 ligase complex, cullins play a role as a scaffold protein and they recruit various substrates. These protein-degron interactions precisely mediate a diverse range of cellular events from cell cycle, through DNA replication to signal transduction. Impairing the proteolysis events were shown to cause severe diseases ranging from autoimmunity to cancer (Rape,2018). FEM1 proteins, including FEM1A/B/C, act as the receptors to specifically recognize C degrons (Yan,2021; Chen,2021; Zhao,2021). Although they share a similar architecture (N- and C-terminal ankyrin domain, tetratricopeptide repeats and von Hippel–Lindau box), they were shown to selectively bind somewhat different C-degrons.

The FEM1 name originates for the nematode worm Caenorhabditis elegans: Most individuals are hermaphrodites but the sex-determining protein fem-1 is essential for male sexual fate (P17221; Spence,1990).
o 5 selected references:

o 8 GO-Terms:

o 2 Instances for DEG_Cend_FEM1B_2
(click table headers for sorting; Notes column: =Number of Switches, =Number of Interactions)
Acc., Gene-, NameStartEndSubsequenceLogic#Ev.OrganismNotes
784 787 ASSPLHIMDFQKWKLIGLQR TP 3 Homo sapiens (Human)
Q15078 CDK5R1
304 307 DLKNESGQEDKKRLLLGLDR TP 5 Homo sapiens (Human)
Please cite: The Eukaryotic Linear Motif resource: 2022 release. (PMID:34718738)

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