ELM - Detail for DEG_Cend_FEM1AC

Accession:	ELME000553
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 prefers 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. Structural analysis of a bound REV_HV1H2 basic peptide (which is not a real C-terminal substrate: 7jya) showed that Arg at position -1 is coordinated via hydrogen bonds and salt bridges to Asp77, Ser117, Arg121 and Asp126 and through cation-π interactions to Phe76 and Phe125. Gln at position -2 forms hydrogen bonds with Arg121. Arg at -3 forms two hydrogen bonds and a salt bridge with Asn183, Asp188 and Glu191, respectively. Further hydrogen bonds with Arg121 and Asn146 stabilize binding with Glu at position -4. Arg at -7 forms electrostatic interactions with Glu191 and Asp211. Mutational analysis revealed that replacing Arg at -1 with Ala drastically reduced binding affinity (Yan,2021). The degron size recognized by FEM1 proteins may be notably larger than other C-degron pathways, or may require a linker to the rest of the protein, as evident from experiments where transplanting the last 25 amino acids was necessary to destabilize a heterologous protein (Lin,2018).
Pattern:	`[RK].{1,2}R$`
Pattern Probability:	`0.0000285`
Present in taxon:	Metazoa

FEM1ABC C-terminal Arg degrons

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 prefers 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.
Structural analysis of a bound REV_HV1H2 basic peptide (which is not a real C-terminal substrate: 7jya) showed that Arg at position -1 is coordinated via hydrogen bonds and salt bridges to Asp77, Ser117, Arg121 and Asp126 and through cation-π interactions to Phe76 and Phe125. Gln at position -2 forms hydrogen bonds with Arg121. Arg at -3 forms two hydrogen bonds and a salt bridge with Asn183, Asp188 and Glu191, respectively. Further hydrogen bonds with Arg121 and Asn146 stabilize binding with Glu at position -4. Arg at -7 forms electrostatic interactions with Glu191 and Asp211. Mutational analysis revealed that replacing Arg at -1 with Ala drastically reduced binding affinity (Yan,2021).
The degron size recognized by FEM1 proteins may be notably larger than other C-degron pathways, or may require a linker to the rest of the protein, as evident from experiments where transplanting the last 25 amino acids was necessary to destabilize a heterologous protein (Lin,2018).

Pattern:

[RK].{1,2}R$

Pattern Probability:

0.0000285

Present in taxon:

Metazoa

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).