ELM—the Eukaryotic Linear Motif resource—2024 update

Kumar, Manjeet; Michael, Sushama; Alvarado-Valverde, Jesús; Zeke, András; Lazar, Tamas; Glavina, Juliana; Nagy-Kanta, Eszter; Donagh, Juan Mac; Kalman, Zsofia E; Pascarelli, Stefano; Palopoli, Nicolas; Dobson, László; Suarez, Carmen Florencia; Van Roey, Kim; Krystkowiak, Izabella; Griffin, Juan Esteban; Nagpal, Anurag; Bhardwaj, Rajesh; Diella, Francesca; Mészáros, Bálint; Dean, Kellie; Davey, Norman E; Pancsa, Rita; Chemes, Lucía B; Gibson, Toby J

doi:10.1093/nar/gkad1058

Cited by 24 publications

(17 citation statements)

References 121 publications

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“…[LIV], also allowing phosphorylation to provide the charges to the termini, as commonly seen in many eukaryotes. However, this fails to take into account that the inner positions strongly select against structure breaking (Pro, Gly) or positively charged (Arg, Lys) amino acids, and also disallow aromatics (Phe, Tyr, Trp, His) at the first intervening position [ 1 , 15 ]. The flanking regions, especially the N-terminal flank, also strongly disfavour positively charged residues.…”

Section: Resultsmentioning

confidence: 99%

Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents

Zeke,

Gibson,

Dobson

2024

PLoS Comput Biol

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The pathogenic, tropical Leishmania flagellates belong to an early-branching eukaryotic lineage (Kinetoplastida) with several unique features. Unfortunately, they are poorly understood from a molecular biology perspective, making development of mechanistically novel and selective drugs difficult. Here, we explore three functionally critical targeting short linear motif systems as well as their receptors in depth, using a combination of structural modeling, evolutionary sequence divergence and deep learning. Secretory signal peptides, endoplasmic reticulum (ER) retention motifs (KDEL motifs), and autophagy signals (motifs interacting with ATG8 family members) are ancient and essential components of cellular life. Although expected to be conserved amongst the kinetoplastids, we observe that all three systems show a varying degree of divergence from their better studied equivalents in animals, plants, or fungi. We not only describe their behaviour, but also build models that allow the prediction of localization and potential functions for several uncharacterized Leishmania proteins. The unusually Ala/Val-rich secretory signal peptides, endoplasmic reticulum resident proteins ending in Asp-Leu-COOH and atypical ATG8-like proteins are all unique molecular features of kinetoplastid parasites. Several of their critical protein-protein interactions could serve as targets of selective antimicrobial agents against Leishmaniasis due to their systematic divergence from the host.

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Section: Resultsmentioning

confidence: 99%

Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents

Zeke,

Gibson,

Dobson

2024

PLoS Comput Biol

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“…Protein interactions between human proteins were obtained from the HIPPIE database [ 47 ]. SLiMs were evaluated using the ELM database [ 48 ], and phosphorylation sites were evaluated using the Phospho ELM database [ 49 ]. Globular domains were obtained from the InterPro annotations of Pfam domains in sequences [ 50 ].…”

Section: Methodsmentioning

confidence: 99%

Structured Tandem Repeats in Protein Interactions

Mac Donagh,

Marchesini,

Spiga

et al. 2024

IJMS

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Tandem repeats (TRs) in protein sequences are consecutive, highly similar sequence motifs. Some types of TRs fold into structural units that pack together in ensembles, forming either an (open) elongated domain or a (closed) propeller, where the last unit of the ensemble packs against the first one. Here, we examine TR proteins (TRPs) to see how their sequence, structure, and evolutionary properties favor them for a function as mediators of protein interactions. Our observations suggest that TRPs bind other proteins using large, structured surfaces like globular domains; in particular, open-structured TR ensembles are favored by flexible termini and the possibility to tightly coil against their targets. While, intuitively, open ensembles of TRs seem prone to evolve due to their potential to accommodate insertions and deletions of units, these evolutionary events are unexpectedly rare, suggesting that they are advantageous for the emergence of the ancestral sequence but are early fixed. We hypothesize that their flexibility makes it easier for further proteins to adapt to interact with them, which would explain their large number of protein interactions. We provide insight into the properties of open TR ensembles, which make them scaffolds for alternative protein complexes to organize genes, RNA and proteins.

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“…However, inaccuracies of computational approaches used to predict PPIs might result from difficulties in the underlying protein structure predictions. Furthermore, many physiologically relevant interactions depend on highly localized, small interfaces, including intrinsically disordered regions (IDRs) [42][43][44][45][46].…”

Section: Introductionmentioning

confidence: 99%

Enhanced Protein-Protein Interaction Discovery via AlphaFold-Multimer

Kim,

Hu,

Comjean

et al. 2024

Preprint

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Accurately mapping protein-protein interactions (PPIs) is critical for elucidating cellular functions and has significant implications for health and disease. Conventional experimental approaches, while foundational, often fall short in capturing direct, dynamic interactions, especially those with transient or small interfaces. Our study leverages AlphaFold-Multimer (AFM) to re-evaluate high-confidence PPI datasets fromDrosophilaand human. Our analysis uncovers a significant limitation of the AFM-derived interface pTM (ipTM) metric, which, while reflective of structural integrity, can miss physiologically relevant interactions at small interfaces or within flexible regions. To bridge this gap, we introduce the Local Interaction Score (LIS), derived from AFM’s Predicted Aligned Error (PAE), focusing on areas with low PAE values, indicative of the high confidence in interaction predictions. The LIS method demonstrates enhanced sensitivity in detecting PPIs, particularly among those that involve flexible and small interfaces. By applying LIS to large-scaleDrosophiladatasets, we enhance the detection of direct interactions. Moreover, we present FlyPredictome, an online platform that integrates our AFM-based predictions with additional information such as gene expression correlations and subcellular localization predictions. This study not only improves upon AFM’s utility in PPI prediction but also highlights the potential of computational methods to complement and enhance experimental approaches in the identification of PPI networks.

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ELM—the Eukaryotic Linear Motif resource—2024 update

Cited by 24 publications

References 121 publications

Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents

Linear motifs regulating protein secretion, sorting and autophagy in Leishmania parasites are diverged with respect to their host equivalents

Structured Tandem Repeats in Protein Interactions

Enhanced Protein-Protein Interaction Discovery via AlphaFold-Multimer

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