Multivalency emerges as a common feature of intrinsically disordered protein interactions

Sipko, Emily L.; Chappell, Garrett F.; Berlow, Rebecca B.

doi:10.1016/j.sbi.2023.102742

Cited by 4 publications

(2 citation statements)

References 87 publications

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“…Their binding modes are often weak and transient, and short linear motifs, encompassing just a few amino acids (usually up to 15) are meanwhile well known to be responsible for many interactions between IDPs/IDRs and their folded partner proteins 27 , 33 , 34 . Remarkably, SLiMs do not always act alone, but often appear in clusters and engage in multivalent interactions 35 , 36 , as for example in nucleo-cytoplasmic trafficking 25 , cellular signaling 37 , and membrane trafficking 38 , including also clathrin mediated endocytosis 5 , 7 , 14 , 21 , 24 .…”

Section: Discussionmentioning

confidence: 99%

An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis

Naudi-Fabra,

Elena-Real,

Vedel

et al. 2024

Nat Commun

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The early phases of clathrin mediated endocytosis are organized through a highly complex interaction network mediated by clathrin associated sorting proteins (CLASPs) that comprise long intrinsically disordered regions (IDRs). AP180 is a CLASP exclusively expressed in neurons and comprises a long IDR of around 600 residues, whose function remains partially elusive. Using NMR spectroscopy, we discovered an extended and strong interaction site within AP180 with the major adaptor protein AP2, and describe its binding dynamics at atomic resolution. We find that the 70 residue-long site determines the overall interaction between AP180 and AP2 in a dynamic equilibrium between its bound and unbound states, while weaker binding sites contribute to the overall affinity at much higher concentrations of AP2. Our data suggest that this particular interaction site might play a central role in recruitment of adaptors to the clathrin coated pit, whereas more transient and promiscuous interactions allow reshaping of the interaction network until cargo uptake inside a coated vesicle.

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Section: Discussionmentioning

confidence: 99%

An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis

Naudi-Fabra,

Elena-Real,

Vedel

et al. 2024

Nat Commun

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“…Further investigation of this possibility is warranted since it could explain several of its properties, in particular those that cannot be attributed to discrete residues or domains. For example, a key feature of intrinsically disordered proteins is their ability to interact with multiple partners [45,69]. This multivalency could explain variously reported interactions (in addition to those explored in this paper) with: DNA [24,70], a catalase [71] and a calmodulin-like factor in tobacco [72], cucumber RNA-directed RNA polymerase 1 [73], an A. thaliana zinc finger protein HB27 [74], and A. thaliana jasmonate ZIM-domain (JAZ) proteins 1, 3, 6, and 10 [75].…”

Section: An Intrinsically Disordered Structure: An Intriguing Possibi...mentioning

confidence: 99%

Investigating the Interactions of the Cucumber Mosaic Virus 2b Protein with the Viral 1a Replicase Component and the Cellular RNA Silencing Factor Argonaute 1

Crawshaw,

Murphy,

Rowling

et al. 2024

Viruses

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The cucumber mosaic virus (CMV) 2b protein is a suppressor of plant defenses and a pathogenicity determinant. Amongst the 2b protein’s host targets is the RNA silencing factor Argonaute 1 (AGO1), which it binds to and inhibits. In Arabidopsis thaliana, if 2b-induced inhibition of AGO1 is too efficient, it induces reinforcement of antiviral silencing by AGO2 and triggers increased resistance against aphids, CMV’s insect vectors. These effects would be deleterious to CMV replication and transmission, respectively, but are moderated by the CMV 1a protein, which sequesters sufficient 2b protein molecules into P-bodies to prevent excessive inhibition of AGO1. Mutant 2b protein variants were generated, and red and green fluorescent protein fusions were used to investigate subcellular colocalization with AGO1 and the 1a protein. The effects of mutations on complex formation with the 1a protein and AGO1 were investigated using bimolecular fluorescence complementation and co-immunoprecipitation assays. Although we found that residues 56–60 influenced the 2b protein’s interactions with the 1a protein and AGO1, it appears unlikely that any single residue or sequence domain is solely responsible. In silico predictions of intrinsic disorder within the 2b protein secondary structure were supported by circular dichroism (CD) but not by nuclear magnetic resonance (NMR) spectroscopy. Intrinsic disorder provides a plausible model to explain the 2b protein’s ability to interact with AGO1, the 1a protein, and other factors. However, the reasons for the conflicting conclusions provided by CD and NMR must first be resolved.

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Investigating the interactions of the cucumber mosaic virus 2b protein with the viral 1a replicase component and the cellular RNA silencing factor Argonaute 1

Crawshaw,

Murphy,

Rowling

et al. 2024

Preprint

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SUMMARYThe cucumber mosaic virus (CMV) 2b protein is a suppressor of plant defenses and a pathogenicity determinant. Amongst the 2b protein’s host targets is the RNA silencing factor Argonaute 1 (AGO1), which it binds to and inhibits. InArabidopsis thaliana, if 2b-induced inhibition of AGO1 is too efficient it induces reinforcement of antiviral silencing by AGO2, and triggers increased resistance against aphids, CMV’s insect vectors. These effects would be deleterious to CMV replication and transmission, respectively, but are moderated by the CMV 1a protein by sequestering sufficient 2b protein molecules into P-bodies to prevent excessive inhibition of AGO1. Mutant 2b protein variants were generated and red and green fluorescent protein fusions used to investigate subcellular colocalization with AGO1 and the 1a protein, and the effects of mutations on complex formation with the 1a protein and AGO1 were investigated using bimolecular fluorescence complementation and co-immunoprecipitation assays. Although we found that residues 56-60 influenced the 2b protein’s interactions with the 1a protein and AGO1, it appears unlikely that any single residue or sequence domain is solely responsible.In silicopredictions of intrinsic disorder within the 2b protein secondary structure were supported by circular dichroism (CD) but not by nuclear magnetic resonance (NMR) spectroscopy. Intrinsic disorder provides a plausible model to explain the 2b protein’s ability to interact with AGO1, the 1a protein and other factors. However, the reasons for the conflicting conclusions provided by CD and NMR must first be resolved.

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Multivalency emerges as a common feature of intrinsically disordered protein interactions

Cited by 4 publications

References 87 publications

An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis

An extended interaction site determines binding between AP180 and AP2 in clathrin mediated endocytosis

Investigating the Interactions of the Cucumber Mosaic Virus 2b Protein with the Viral 1a Replicase Component and the Cellular RNA Silencing Factor Argonaute 1

Investigating the interactions of the cucumber mosaic virus 2b protein with the viral 1a replicase component and the cellular RNA silencing factor Argonaute 1

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