ELM-the eukaryotic linear motif resource in 2020

Abstract

The eukaryotic linear motif (ELM) resource is a repository of manually curated experimentally validated short linear motifs (SLiMs). Since the initial release almost 20 years ago, ELM has become an indispensable resource for the molecular biology community for investigating functional regions in many proteins. In this update, we have added 21 novel motif classes, made major revisions to 12 motif classes and added >400 new instances mostly focused on DNA damage, the cytoskeleton, SH2-binding phosphotyrosine motifs and motif mimicry by pathogenic bacterial effector proteins. The current release of the ELM database contains 289 motif classes and 3523 individual protein motif instances manually curated from 3467 scientific publications. ELM is available at: http://elm.eu.org.

Figure 1.

(A) Progression of the motif classes and instances integrated in the ELM resource. (B) Pie-chart showing count and proportion of new instance addition from each motif class type in the current ELM release. (C) Barplot showing the motif classes grouped according to the coverage of their instances by PDB structures, only one structure per instance has been considered for showing the coverage. In total, 164 ELM classes are covered by at least one structure. (D) Top 20 motif classes in terms of the number of representative PDB structures are shown. The plots were generated using plotly chart studio (https://chartstudio.plot.ly).

Figure 2.

Structural information on representative DNA damage and repair motif instances and classes added in the current ELM update. (A) Structure of PCNA trimer in complex with PIP box of ZRANB3 [PDB ID: 5MLO] (77). (B) Closeup of the structure of PCNA PIP-binding pocket in complex with the PIP box of p21 [PDB ID: 1AXC] (34). (C) Close-up of the structure of PCNA PIP-binding pocket in complex with the APIM of ZRANB3 [PDB ID: 5YD8] (33). The blue residue in panels (B) and (C) shows the rearrangement of a leucine 126 in the PIP-binding pocket to accommodate the APIM peptide. (D) Close-up of the structure of the Rev1 C-terminal domain with the RIR motif of DNA polymerase kappa [PDB ID: 4FJO] (78). (E) Close-up of the structure of the C-terminal domain of the yeast MUTL alpha (MLH1/PMS1) bound to MIP box motif of Exo1 [PBD ID: 4FMO] (79). (F) Peptides from the structures of panels (A–E) aligned around their core hydrophobic residues. Underlined residues define the motif consensus residues in the peptide. Structural figures were prepared using the UCSF Chimera software (80).

Figure 3.

Setting up the ELM server correctly to query bacterial effectors for SLiM candidates using, as an example, the IDP-rich TarP effector from Chlamydophila caviae for which the natural host is guinea pig. TarP is extracellular for the bacterium but the correct cell compartment to use is cytosol for the host cell. The correct species is the host Cavia porcellus. In the output, the three recently added VBS motifs (41) are shown as red ovals. All other motif matches are hypothetical.

Figure 4.

Motif-mediated interactions of the Actin Cytoskeleton network. The KEGG resource network for Regulation of Actin Cytoskeleton (KEGG:hsa04810) is color-coded by ELM motif classes. Proteins of the pathway have a light mint green color by default. Motif-containing proteins are re-colored as follows: DOC class (docking sites) - moderate blue; LIG class (ligand binding motifs) - vivid orange; MOD class (modification sites) - soft pink; DEG class (degradation sites) - yellow; CLV class (cleavage sites) - very soft blue; TRG class (targeting sites) - pure orange; proteins with motifs belonging to multiple classes are marked with the respective colors as described in the bottom right of the figure. ELM has instances for pathogen hijack of actin polymerization at VCL, IRSp53, NWASP and Actin itself. The pathogen proteins affecting these hotspots are shown in the rounded boxes colored with light orange background.