The disordered boundary of the cell: emerging properties of membrane-bound intrinsically disordered proteins

Mohammad, Irrem-Laareb; Mateos, Borja; Pons, Miquel

doi:10.1515/bmc-2019-0003

Cited by 10 publications

(6 citation statements)

References 63 publications

(78 reference statements)

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“…This suggests that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs. Previous studies have demonstrated that IDRs are more abundant in membrane proteins than in the complete proteome, with more than 50% of transmembrane proteins containing IDRs composed of at least 30 residues [ 15 , 16 ]. Our results show that Group 2 transmembrane proteins exhibit the second-highest degree of disorder, confirming this finding.…”

Section: Discussionmentioning

confidence: 99%

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Lee

Procopio

Pulido

et al. 2023

IJMS

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Intrinsically disordered regions (IDRs) are protein regions that are unable to fold into stable tertiary structures, enabling their involvement in key signaling and regulatory functions via dynamic interactions with diverse binding partners. An understanding of IDRs and their association with biological function may help elucidate the pathogenesis of inherited retinal diseases (IRDs). The main focus of this work was to investigate the degree of disorder in 14 proteins implicated in IRDs and their relationship with the number of pathogenic missense variants. Metapredict, an accurate, high-performance predictor that reproduces consensus disorder scores, was used to probe the degree of disorder as a function of the amino acid sequence. Publicly available data on gnomAD and ClinVar was used to analyze the number of pathogenic missense variants. We show that proteins with an over-representation of missense variation exhibit a high degree of disorder, and proteins with a high amount of disorder tolerate a higher degree of missense variation. These proteins also exhibit a lower amount of pathogenic missense variants with respect to total missense variants. These data suggest that protein function may be related to the overall level of disorder and could be used to refine variant interpretation in IRDs.

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Section: Discussionmentioning

confidence: 99%

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Lee

Procopio

Pulido

et al. 2023

IJMS

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“…Today it is well accepted that membrane deformations and associated protein functions are coupled mechanisms (Haylock et al, 2020;Song et al, 2019), with complex emergent properties derived in part from the highly heterogeneous nature of the bilayers (Nicolson, 2014;Mohammad et al, 2019), or as suggested by Lamparter and Galic (2020), a versatile, adaptive composite material. Membrane proteins may dynamically modify their curvature preference upon external stimuli (Stroh and Risselada, 2021), also making the coupled mechanism dynamic.…”

Section: Discussionmentioning

confidence: 99%

Enhanced sampling for lipid-protein interactions during membrane dynamics

Masone¹

2023

Biocell

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The inflexible concept of membrane curvature as an independent property of lipid structures is today obsolete.Lipid bilayers behave as many-body entities with emergent properties that depend on their interactions with the environment. In particular, proteins exert crucial actions on lipid molecules that ultimately condition the collective properties of the membranes. In this review, the potential of enhanced molecular dynamics to address cell-biology problems is discussed. The cases of membrane deformation, membrane fusion, and the fusion pore are analyzed from the perspective of the dimensionality reduction by collective variables. Coupled lipid-protein interactions as fundamental determinants of large membrane remodeling events are also commented. Finally, novel strategies merging cell biology and physics are considered as future lines of research.

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Section: Asymmetric Distribution Of Charged Lipids In Membranesmentioning

confidence: 99%

“…The strong electrostatic field in the vicinity of the membrane (10 5 Vcm −1 ) [11] can substantially change the conformational landscape, triggering additional interactions, especially in intrinsically disordered proteins with multiple charged residues [2]. Interestingly, various toxins interacting with the outer leaflet, enriched in phosphatidylcholine headgroups, have tyrosine residues participating in cation-p interactions with the positively charged choline headgroup [15,16].…”

Section: Asymmetric Distribution Of Charged Lipids In Membranesmentioning

confidence: 99%

“…Lipids play an active role in signaling, supported by the presence of at least 800 distinct species in a typical mammalian cell membrane, responding to culture conditions and cell [1]. The abundance of intrinsically disordered regions permanently or transiently bound to the membrane is one characteristic of the membrane periphery, described as the "disordered boundary of the cell" [2]. In fact, intrinsically disordered regions (IDR) longer than 30 residues are more abundant in the subset of intrinsic membrane proteins (57%) than in the complete human proteome (34%), suggesting that around 45% of IDRs belong to proteins with transmembrane regions.…”

Section: Introductionmentioning

confidence: 99%

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Basic Residue Clusters in Intrinsically Disordered Regions of Peripheral Membrane Proteins: Modulating 2D Diffusion on Cell Membranes

Pons

2021

Physchem

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A large number of peripheral membrane proteins transiently interact with lipids through a combination of weak interactions. Among them, electrostatic interactions of clusters of positively charged amino acid residues with negatively charged lipids play an important role. Clusters of charged residues are often found in intrinsically disordered protein regions, which are highly abundant in the vicinity of the membrane forming what has been called the disordered boundary of the cell. Beyond contributing to the stability of the lipid-bound state, the pattern of charged residues may encode specific interactions or properties that form the basis of cell signaling. The element of this code may include, among others, the recognition, clustering, and selective release of phosphatidyl inositides, lipid-mediated protein-protein interactions changing the residence time of the peripheral membrane proteins or driving their approximation to integral membrane proteins. Boundary effects include reduction of dimensionality, protein reorientation, biassing of the conformational ensemble of disordered regions or enhanced 2D diffusion in the peri-membrane region enabled by the fuzzy character of the electrostatic interactions with an extended lipid membrane.

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The disordered boundary of the cell: emerging properties of membrane-bound intrinsically disordered proteins

Cited by 10 publications

References 63 publications

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Initial Investigations of Intrinsically Disordered Regions in Inherited Retinal Diseases

Enhanced sampling for lipid-protein interactions during membrane dynamics

Basic Residue Clusters in Intrinsically Disordered Regions of Peripheral Membrane Proteins: Modulating 2D Diffusion on Cell Membranes

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