The Structural and Functional Diversity of Intrinsically Disordered Regions in Transmembrane Proteins

Appadurai, Rajeswari; Uversky, Vladimir N.; Srivastava, Anand

doi:10.1007/s00232-019-00069-2

Cited by 16 publications

(12 citation statements)

References 283 publications

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“…Due to the high distribution of cwpFM in pathogenic but also non-pathogenic strains, it is hard to use the detection of the cwpFM gene as a biomarker of pathogenicity. However, an accurate bioinformatics comparison between the sequences of our strain collection was performed, and then the residues distinct between non-pathogenic, FBO and clinical strains were mapped onto the homology model of CwpFM to check if the sequence and 3D structure could correlate with the pathogenicity of a strain [60]. All CwpFMs from B. cereus display four intrinsically disordered linkers (IDL) as connectors between SH3b and/or NLPC_P60 domains.…”

Section: Discussionmentioning

confidence: 99%

Structural Modeling of Cell Wall Peptidase CwpFM (EntFM) Reveals Distinct Intrinsically Disordered Extensions Specific to Pathogenic Bacillus cereus Strains

Tran

Cormontagne

Vidić

et al. 2020

Toxins

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The emergence of B. cereus as an opportunistic food-borne pathogen has intensified the need to distinguish strains of public health concern. The heterogeneity of the diseases associated with B. cereus infections emphasizes the versatility of these bacteria strains to colonize their host. Nevertheless, the molecular basis of these differences remains unclear. Several toxins are involved in virulence, particularly in gastrointestinal disorders, but there are currently no biological markers able to differentiate pathogenic from harmless strains. We have previously shown that CwpFM is a cell wall peptidase involved in B. cereus virulence. Here, we report a sequence/structure/function characterization of 39 CwpFM sequences, chosen from a collection of B. cereus with diverse virulence phenotypes, from harmless to highly pathogenic strains. CwpFM is homology-modeled in silico as an exported papain-like endopeptidase, with an N-terminal end composed of three successive bacterial Src Homology 3 domains (SH3b1–3) likely to control protein–protein interactions in signaling pathways, and a C-terminal end that contains a catalytic NLPC_P60 domain primed to form a competent active site. We confirmed in vitro that CwpFM is an endopeptidase with a moderate peptidoglycan hydrolase activity. Remarkably, CwpFMs from pathogenic strains harbor a specific stretch of twenty residues intrinsically disordered, inserted between the SH3b3 and the catalytic NLPC_P60 domain. This strongly suggests this linker as a marker of differentiation between B. cereus strains. We believe that our findings improve our understanding of the pathogenicity of B. cereus while advancing both clinical diagnosis and food safety.

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Section: Discussionmentioning

confidence: 99%

Structural Modeling of Cell Wall Peptidase CwpFM (EntFM) Reveals Distinct Intrinsically Disordered Extensions Specific to Pathogenic Bacillus cereus Strains

Tran

Cormontagne

Vidić

et al. 2020

Toxins

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“…Ion channel IDRs are important allosteric modulators of channel activity ( 83 , 84 , 85 ) as well as sites for scaffolding protein interactions ( 86 , 87 , 88 ). Furthermore, protein IDRs are often hot spots for PTMs ( 89 ), which can affect the target protein’s binding partners and structural conformation ( 90 ).…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, protein IDRs are often hot spots for PTMs ( 89 ), which can affect the target protein’s binding partners and structural conformation ( 90 ). Ubiquitination of protein IDRs is well studied, and evolutionarily conservation of Ub sites within IDRs is favored over ordered regions ( 91 ), although the effects of ion channel IDR ubiquitination on channel function are not well explored ( 33 , 87 ). However, there are numerous examples of monoubiquitination regulating protein function through alteration of protein–protein and protein–lipid interactions in other contexts ( 18 , 19 , 20 , 92 , 93 ), suggesting that monoubiquitination of the TRPV4 N-terminal IDR may similarly influence channel activity through effects on protein or membrane lipid interactions without affecting surface localization.…”

Section: Discussionmentioning

confidence: 99%

Multiubiquitination of TRPV4 reduces channel activity independent of surface localization

Aisenberg

McCray

Sullivan

et al. 2022

Journal of Biological Chemistry

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“…Indeed, few aspects of NKA functional regulation have been attributed to discrete structural elements. Future studies that attempt to discover unifying principles of FXYD protein regulation of NKA may benefit from strategies developed for investigation of intrinsically disordered proteins ( Appadurai et al, 2019 ).…”

Section: Introductionmentioning

confidence: 99%

FXYD proteins and sodium pump regulatory mechanisms

Yap

Šeflová

Sweazey

et al. 2021

Journal of General Physiology

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The sodium/potassium-ATPase (NKA) is the enzyme that establishes gradients of sodium and potassium across the plasma membrane. NKA activity is tightly regulated for different physiological contexts through interactions with single-span transmembrane peptides, the FXYD proteins. This diverse family of regulators has in common a domain containing a Phe-X-Tyr-Asp (FXYD) motif, two conserved glycines, and one serine residue. In humans, there are seven tissue-specific FXYD proteins that differentially modulate NKA kinetics as appropriate for each system, providing dynamic responsiveness to changing physiological conditions. Our understanding of how FXYD proteins contribute to homeostasis has benefitted from recent advances described in this review: biochemical and biophysical studies have provided insight into regulatory mechanisms, genetic models have uncovered remarkable complexity of FXYD function in integrated physiological systems, new posttranslational modifications have been identified, high-resolution structural studies have revealed new details of the regulatory interaction with NKA, and new clinical correlations have been uncovered. In this review, we address the structural determinants of diverse FXYD functions and the special roles of FXYDs in various physiological systems. We also discuss the possible roles of FXYDs in protein trafficking and regulation of non-NKA targets.

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The Structural and Functional Diversity of Intrinsically Disordered Regions in Transmembrane Proteins

Cited by 16 publications

References 283 publications

Structural Modeling of Cell Wall Peptidase CwpFM (EntFM) Reveals Distinct Intrinsically Disordered Extensions Specific to Pathogenic Bacillus cereus Strains

Structural Modeling of Cell Wall Peptidase CwpFM (EntFM) Reveals Distinct Intrinsically Disordered Extensions Specific to Pathogenic Bacillus cereus Strains

Multiubiquitination of TRPV4 reduces channel activity independent of surface localization

FXYD proteins and sodium pump regulatory mechanisms

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