Table 1.

Table 2.

SLiMs in RNA processing and decay

In eukaryotic cells, numerous RNA processing and modification events are required to produce RNAs in their final functional forms. To remove defective, unstable or unwanted transcripts from the nucleus, RNAs must first be identified and then degraded by the nuclear exosome (39), a multi-component protein complex of RNA processing enzymes.

The RNA helicase Mtr4 is an important cofactor of the nuclear exosome (20,40,41). Mtr4 is not just a helicase but rather a multi-domain, modular hub protein (20) that contributes to the processing of ribosomal RNAs (42) and the targeting of the exosome to different degradable RNA species (40). Mtr4 is part of the TRAMP complex, together with the Trf4 poly(A)polymerase and the Air2 RNA-binding adaptor protein (40,43). Most of the hitherto discovered SLiMs associated with nuclear RNA surveillance are either mediating the inter-subunit interactions of the TRAMP complex or facilitating the recruitment of the complex by diverse nuclear exosome cofactors (Figure2).

A highly conserved motif within the N-terminal tail of yeast Trf4 interacts with the helicase core of Mtr4 (see the LIG_Mtr4_Trf4_1 motif class; (40)). This interaction is conserved in vertebrates, although with slightly different motif sequence preferences (see LIG_Mtr4_Trf4_2). Within the N-terminal tail of Air2 there are two distinct Mtr4-interacting motifs, one interacts with the helicase core (LIG_Mtr4_Air2_1) (40), while the other can bind to the KOW domain within the arch of Mtr4 (LIG_Mtr4_AIM_1) (40). This newly added, so-called arch-interacting motif (AIM; LIG_Mtr4_AIM_1) is particularly important, because many nuclear exosome cofactors, such as Nop53, Utp18 and Sqs1 also employ this motif for binding to and recruiting Mtr4 and the exosome to specific RNA transcripts to be degraded (41,44). Furthermore, this mode of interaction is also conserved in vertebrates (20,45). In the TRAMP complex, the Air proteins, Air1 or Air2, interact with Trf4 through a conserved motif within the linker between their fourth and fifth zinc knuckles (LIG_Trf4_IWRxY_1) plus their fifth zinc knuckle itself (46,47). Trf4 also contributes to the targeting of complexes for the degradation of incorrectly folded non-coding RNAs. The C-terminal Nrd1-interacting motif (NIM) of Trf4 binds to the NNS (Nrd1-Nab3-Sen1) complex subunit Nrd1 (48). This NIM motif class (LIG_Nrd1CID_NIM_1) has now been extensively revised, since the NNS subunit Sen1 (49) and exosome-associated RNA-binding protein Mpp6 (50) also turned out to employ NIM motifs for the binding of Nrd1.

Besides the TRAMP complex, additional RNA processing complexes have been characterised. In the yeastS. pombe, the MTREC (Mtl1–Red1 core) complex is responsible for directing the degradation of meiotic, non-coding and unspliced RNAs (51–53). Mtl1 (Mtr4-like protein 1) is a homolog of Mtr4. Red1 protein (54) interacts with Mtr1 and additional proteins in the MTREC complex, including zinc-finger containing protein Ars2 (52). Red1 contains an EDGEI motif (see newly annotated class LIG_ARS2_EDGEI_1) that is responsible for its interaction with Ars2.

In humans, there are a myriad of binding partners that interact with the human homolog of yeast Ars2, the Serrate RNA effector molecule homolog protein, through one or more EDGEI motifs. The binding of these partners facilitates different RNA processing activities (55–57). Interestingly, there are examples of EDGEI-mediated interactions even inA. thaliana andD. melanogaster; therefore they seem to be highly conserved across evolution.

Protein degradation

Protein quality control mechanisms are of quintessential importance to all living cells and their representation is becoming increasingly important for the ELM resource. Targeted degradation of proteins can remove unwanted, mis-translated polypeptides, improperly localised, fragmented or misfolded proteins, proteins from viral intruders, and many more (Figure3) (58). Protein degradation within the eukaryotic cytoplasm and nucleus (and even of proteins translocated from the endoplasmic reticulum) is performed by the ubiquitin-proteasome system (59). Ubiquitination is orchestrated by at least three families of enzymes, E1 ubiquitin activating and E2 and E3 ubiquitin conjugating enzymes, which act sequentially, in distinct complexes (60) to add lysine 48 (K48)-linked polyubiquitin chains to the target protein. E3 ligases recognise their target proteins through molecular features called degrons. The majority of known degrons are SLiMs, and many of them are located at the protein amino (N-degrons) or carboxy (C-degrons) terminus (61). Most N‐terminal degrons are well known (explaining the so-called ‘N-end-rule’ determining protein half-life in eukaryotic cells) (62). However, C-degron pathways that selectively degrade proteins depending on the amino acids preceding their C-termini, also referred to as DesCEND (Destruction via C‐End Degron) pathways, have also been identified in recent years (58). The existence of C-terminal degrons explains why the distribution of C-terminal amino acids is unevenly biased in the proteome, as protein evolution actively selects against destabilising residues unless functionally required (63). So far, terminal Gly, Ala, Arg and Glu residues (‘destabilising residues’) are known to form parts of C-end degrons, being recognised by specific ubiquitin ligases (62,63).

C‐degron SLiMs consist of a few (typically only 2) conserved residues. A C‐terminal location and high structural accessibility (local disorder) are essential for C‐degrons to trigger degradation (58). C-terminal degrons can sometimes be present at the native C-termini of proteins or can be introduced by alternative mechanisms including premature translation termination or post-translational modifications (64,65). Terminal degron signals can also initially be internal, being latently present within the protein sequence and becoming exposed following proteolytic cleavage. E3 ligases recognising C-end degrons can be single- or multi-subunit molecules, like cullin-RING ligases (CRLs). The list of ubiquitin ligases and recognition subunits known to be associated with DesCEND pathways is extensive: KLHDC1/2/3/10, FEM1A/B/C, DCAF12, APPBP2, TRPC4AP, TRIM7, PIRH2, etc. (63,64,66,67). Unfortunately, not all E3 ligase substrate preferences have been sufficiently explored. The current ELM update includes new motif class definitions for the C-end recognition motifs of the DCAF12, FEM1A, FEM1B, FEM1C, KLHDC2 and TRIM7 ubiquitin E3 ligases (Table2). Below we briefly discuss the DCAF12 and KLHDC2 cases.

The cullin 4-RING (CRL4) ubiquitin ligases are highly modular and associate to various substrate recognition subunits (termed DCAFs) through their shared subunit DDB1. DCAF12 has been found to recruit proteins with a C-terminal di-Glu motif (Glu-Glu-COOH). Known substrates of CRL4^DCAF12 Cullin-RING E3 ligase include CCT5, a member of the T-complex protein ring (TRiC) chaperonin complex (68), as well as the MAGE-A3 and MAGE-A6 melanoma-associated antigens, involved in the regulation of ubiquitylation and autophagy (69). In all these examples, the extreme C-terminus of the substrate protein is bound tightly at the center of the WD40 domain of DCAF12, by a positively charged coronet of lysine (K91, K108, K254 in PDB: 8AJM/8AJO) and arginine (R203, R256, R344 in PDB: 8AJM/8AJO) residues (68). However, other, yet-unknown recognition modes might also exist for DCAF12, explaining its interaction with IAPs helping cell survival (70) or MOV10 involved in multiple cellular roles (71).

The KLHDC1, KLHDC2, KLHDC3 and KLHDC10 proteins are closely related vertebrate cullin 2 (Cul2) or cullin 5 (Cul5) RING (CRL2/CRL5) ubiquitin ligase substrate recognition subunits, binding C-terminal degrons ending in glycine with distinct but overlapping specificities. Out of this group, KLHDC2 is the best characterised protein, associated with Cul2, responsible for the recognition of substrates ending in a di-Gly (Gly-Gly-COOH) motif. Structural studies reveal that the degron is bound to the center of the Kelch repeat domain, with the twin arginines (R236 and R241 in PDB: 6DO3/6DO4/6DO5) coordinating the C-terminal carboxylate (65). The size of this pocket is restricted to binding either GG$ or (rarely seen) GA$ motifs (72). The last 6 amino acids also contact the surface, but there is relatively less restriction imposed on them, except for a preference for small side chains.

Interestingly, Di-Gly degrons (or Gly-Ala degrons), substrates of CRL2^KLHDC2 can be generated by at least three distinct physiological processes. Some rare proteins natively end in two glycines, such as EPHB2 (73). These motifs can also be generated by proteolysis, as they are compatible with the substrates processed by certain ubiquitin-specific proteases, including an autoprocessing site in USP1 (65). Several selenoproteins can also suffer premature termination in case of selenium starvation, precluding the physiological overriding of the stop codons by selenocysteinyl-tRNAs (74). Selenoprotein K (SelK) and Selenoprotein S (SelS), when terminated prematurely, will end in a di-Gly motif, that is targeted by KLHDC2 (as well as other, related subunits) for ubiquitylation and destruction (65,74). Finally, KLHDC2 has also been shown to recognize its C-terminus (Gly-Ser-COOH) due to its resemblance to a degron, leading to the formation of inactive oligomers (73), adding a further layer of regulation to this already complicated system.

Endoplasmic reticulum (ER)-associated degradation (ERAD)

Similar to degron-mediated protein destruction, the endoplasmic reticulum (ER)-associated degradation (ERAD) pathway functions as a guardian of exported and vesicular protein quality. This pathway differentiates between folded and misfolded proteins inside the ER lumen (75) and shuttles problematic proteins into the cytosol through membrane channels in an energy-dependent manner. Therefore, malfunctioning of the ERAD pathway can lead to the accumulation of defective proteins, a condition implicated in >60 diseases that include neurological disorders, cancer, and cystic fibrosis (76). Moreover, many viruses, including several Nidovirales species such as coronaviruses, hijack the ERAD machinery during viral replication while simultaneously evading immune detection by the host. Viruses exploit ER membrane-derived structures, such as double-membrane vesicles (DMVs), to conceal viral RNA from cytosolic cellular sensors responsible for initiating interferon production and innate immunity responses (77,78).

Prior to their elimination, most ERAD substrates are tagged with ubiquitin chains, which then serve as docking sites for VCP (Valosin-Containing Protein, also known as P97/TERA). VCP is an abundant protein (among the top 5% of cellular proteins) of the AAA+-ATPase group. It regulates various cellular processes, ranging from protein quality control to supporting DNA damage response and membrane trafficking. Importantly, VCP mutations have been linked to diseases characterised by protein aggregation, including Multisystem Proteinopathy (MSP), Familial Amyotrophic Lateral Sclerosis (fALS), and Charcot-Marie-Tooth Disease Type2Y (CMT2Y) (79). Essential to VCP’s interactions is its N-terminal domain (VCPN), which acts as a hub for binding various adaptor proteins. These interactions happen through three known motifs: VIM (VCP-Interacting Motif), VBM (VCP-Binding Motif), and the SHP box. These three motifs have been added as new ELM classes in the current update (Table2). Notably, the VIM motif is hallmarked by a sequence module flanked on both sides with arginine preferences and a hydrophobic centre with conserved alanine residues. The VBM motif shows similarities with VIM in its arginine-rich amino acid content and interacts with the exact same VCP surface. In contrast, the SHP box forms a short, antiparallel β-strand, which augments the β-sheet of VCP’s NTD subdomain at a site distinct from the two other VCP-binding motifs. VCP itself has the newly annotated Pub domain Interacting (PIM) motif that docks to the E3 ligase HOIL-1-interacting protein (HOIP), a part of the Linear ubiquitin chain assembly complex (LUBAC) which modulates the NF-κB pathway (80).

Update to the Kinase substrate specificities in ELM

In the current ELM update, we have added two new classes that define the phosphorylation site specificity of two kinases. One class represents the substrates of two Ser/Thr directed kinases, Adaptor-Associated kinase 1 (AAK1) and BMP-2 Inducible Kinase (BIKe/BMP2K). The second class defines the specificity of the Lymphocyte-oriented kinase (LOK), also named STK10 (Table2).

AAK1 and BIKe/BMP2K are endocytic kinases that regulate diverse cellular functions, including receptor-mediated endocytosis, Notch pathway regulation, and dendrite morphogenesis. These kinases preferentially phosphorylate threonine residues and phosphorylate the QxTG motif present in the adaptor-related protein complex mu2 subunit (AP2M1) (81). Endocytic functions of these kinases also enable them to play a crucial role in controlling intracellular trafficking during the SARS-CoV-2 infection and entry process (82). Hepatitis C virus (HCV) and dengue virus (DENV) are other examples where these kinases are involved in viral entry and assembly/egress processes (83,84). The motif preference of the AAK1 and BIKe kinases is known from peptide SPOT arrays and other low-throughput in-vitro kinase assays (28,81,84–87) and indicates a strong preference for a Gly residue at the T + 1 position, Gln at the T – 2 position and Ile at the T – 5 position. Prk1p, the yeast homolog of AAK1/BIKe kinases, phosphorylates the Pan1p, Sla1p, and Scd5p substrates which all contain a similar phosphorylation motif (88–90).

LOK/STK10 regulates cytoskeletal dynamics in addition to affecting the cell shape and movements. An example of the latter includes its role in lymphocyte migration and microvilli formation in epithelial cells, which is achieved via phosphorylating the ERM proteins (Ezrin, Radixin and Moesin). Defining the specificity determinants of the LOK phosphosites is challenging due to the high sequence conservation of the C-terminal ERM protein regions, which contain the target phosphosites. Nevertheless, experiments from Belkinaet al. (91) and SPOT arrays from Johnson JLet al. (28) reveal that LOK preferentially phosphorylates Thr over Ser residues. LOK sequence preferences around the phosphosite include Tyr at the T-2 position, large hydrophobic or aromatic amino acids at the T + 1 position and positively charged amino acids in the T – 3 and T + 2 positions flanking the phosphosite.

In addition to the two kinase classes with Thr site-specificity, a substantial update has been done to three classes describing the specificity for NEK (MOD_NEK2_1 and MOD_NEK2_2) and DNA damage signalling (MOD_PIKK_1) kinases. (Table2). The ELM kinome update was assisted by the availability of a recent comprehensive assessment of the human Ser/Thr kinome using SPOT array technology (28), where the phosphosite preferences for 303 kinases have been profiled. This provides a unique opportunity to further improve kinase motif definitions in ELM by integrating these SPOT arrays with existing experimentally identified phosphosites.

Receptor tyrosine kinases (RTKs) regulate proliferation and actin cytoskeleton remodelling in response to extracellular signals. RTKs become autophosphorylated in tyrosine residues (pTyr) and relay the signal to non-receptor Src-family kinases (SFKs) (92) and adaptor proteins such as NCK1/2 (93), among others. This first step is achieved through binding of pTyr motifs to Src-homology 2 (SH2) domains present in SFKs and NCK1/2. The human proteome contains over 100 SH2 domains which bind defined ligands but present a significant degree of cross specificity (94,95). The present ELM update adds an extensive revision of the NCK (LIG_SH2_NCK_1) and SFK (LIG_SH2_SFK_2) specificity classes, as well as a new class describing the autoinhibitory interaction involving the C-tail of SFKs (LIG_SH2_SFK_CTail_3). The loss of the C-tail interaction leads to oncogenic activation in v-SRC. Viral and bacterial pathogens also mimic SFK and NCK SH2 motifs to induce cell proliferation and actin cytoskeleton remodelling (96).

SLiMs in innate immunity

The human cell must be able to respond to many different types of pathogens and the tell-tale signs of infection that they provide (97). Within the cytosol of the cell, these can include both DNA (cGAS-STING) or dsRNA detectors (RIGI-MAVS) that control whether interferon regulatory factors (IRFs) can activate transcription (98,99). However, cells that are not already primed to expect pathogen invasion are most likely to succumb to the invader. Additionally, therefore, the cell surface is equipped with Tumour necrosis family receptors, Toll-like receptors, Interferon receptors and so forth so that it can be alerted to the presence of pathogens in the body and rapidly initiate defensive signalling internally, including transcriptional activation of critical defence genes such as interferons and cytokines by transcription factors such as NF-κB (97,100).

The canonical NF-κB activation pathway begins by an activated TNF superfamily receptor trimerising and recruiting a combination of TRAF family E3 ligases via TRAF-binding motifs such as PxQ variants in the cytosolic tails (Table2). Unlike most E3 ligases, the Lysine-63 ubiquitin chains generated by the TRAFs are activating, rather than destructive signals. The pathway proceeds via IKK protein kinase activation and IκB protein kinase degradation, ultimately releasing the NF-κB RelA component for nuclear entry and gene activation. The non-canonical pathway involves TNFR recruitment of a partially distinct subset of TRAFs and ultimately releasing the NF-κB component RelB into the nucleus for gene activation (101). These pathways involve communication between several multiprotein complexes but are typically shown as rather linear.

The RIGI-MAVS detection systems for cytosolic pathogen dsRNA are present on the mitochondrial membrane's outer surface (102). The cGAS-STING detection systems for cytosolic pathogen DNA are also present on the mitochondrial outer membrane (but also the endoplasmic reticulum) (99). Both of these systems control interferon regulatory factors, using the phosphorylated LxI (pS) SLiM (Table2) to keep the IRFs in the cytosol as long as there are no pathogenic nucleic acid signals. Most of the IRF protein family have the same SLiM and, when phosphorylated by TBK1 or IKKϵ at the SLiM itself, they homodimerise and escape the cytosol into the nucleus where they can bind and oligomerise the general transcription factors P300/CBP and together stimulate interferon gene transcription (103).

There are many complications to the innate immunity systems simplistically described above - for example, they connect to each other via some of their SLiM-mediated interactions. One of the strongest connections is through the TANK Binding Kinase (TBK1). Currently, the only biophysically identified SLiM binder to TBK1 is STING, which interacts via a TBK1 docking motif (DOC_TBK1_STING_1) (104). The acronym TANK is derived directly from NF-κB regulation (TRAF family member-associated NF-kappa-B activator), but TANK and TBK1 are reported to be core components of an IRF3 activation complex (105). Figure4 shows a network of twenty close interactors with TBK1: Multiple interactions unite the NF-κB and IRF gene activation pathways. These closely connected anti-pathogen systems (98) illustrate why it is essential to think in terms of regulatory networks (where vertical pathways represent specific routes of information flow that can be controlled by any number of lateral interactions subject to other cell state conditions), as well as the fundamental importance of different SLiM classes in how network state is being modulated (2,106).

Impact of AlphaFold on SLiM bioinformatics

AlphaFold has proved to be an effective predictor of IDRs (107). ELM annotators now routinely use available structure predictions from the AlphaFold database (108,109) as they aid assessing SLiM instance plausibility, taking advantage of properties such as estimated disorderliness (a low pLDDT score) (109). AlphaFold prediction results have recently been incorporated into LeishMANIAdb (110) to more precisely score the probability of putative SLiMs inLeishmania species proteomes, that might interact with host proteins.

In addition there is increasing interest in using AlphaFold forde novo modelling of putative SLiM interactions with known or potential interaction domains. For example, in a recent C degron study, AlphaFold was used to model the interaction site of a POLD2 Proline C degron on FEM1B, predicting a distinct binding site to the better studied Arginine C-degron (72). In a benchmarking study of a protein-peptide interaction dataset, AlphaFold2-Multimer achieved only 40% success rate in modelling the correct binding site and interface by default protocol. However, the accuracy was enhanced with a combination of prediction modes, which included different protocols to incorporate the peptide alignment information while modelling the protein–peptide complex (111). In a second study, an ELM-derived dataset was used to test the accuracy of AlphaFold-Multimer in modelling SLiM interactions, finding that a fragment-based approach around the interacting SLiM region can enhance the performance of modelling SLiMs (112). We expect the application of AlphaFold for SLiM prediction will be a growing area of bioinformatics research.

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Data Availability Statement

ELM is available at:http://elm.eu.org.