Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels

Zeyer, Karina A.; Reinhardt, Dieter P.

doi:10.1016/j.mrrev.2015.04.002

Cited by 38 publications

(36 citation statements)

References 95 publications

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“…The perturbation results in short‐ or long‐range structural rearrangements and can affect the Ca 2+ binding ability of the domain. This can lead to increased susceptibility to proteolysis, retention in the endoplasmic reticulum, and delayed secretion . It has been suggested that increased oxidative stress can contribute to disease progression .…”

Section: Resultsmentioning

confidence: 99%

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

et al. 2019

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Recently developed quantitative redox proteomic studies enable the direct identification of redox‐sensing cysteine residues that regulate the functional behavior of target proteins in response to changing levels of reactive oxygen species. At the molecular level, redox regulation can directly modify the active sites of enzymes, although a growing number of examples indicate the importance of an additional underlying mechanism that involves conditionally disordered proteins. These proteins alter their functional behavior by undergoing a disorder‐to‐order transition in response to changing redox conditions. However, the extent to which this mechanism is used in various proteomes is currently unknown. Here, a recently developed sequence‐based prediction tool incorporated into the IUPred2A web server is used to estimate redox‐sensitive conditionally disordered regions at a large scale. It is shown that redox‐sensitive conditional disorder is fairly widespread in various proteomes and that its presence strongly correlates with the expansion of specific domains in multicellular organisms that largely rely on extra stability provided by disulfide bonds or zinc ion binding. The analyses of yeast redox proteomes and human disease data further underlie the significance of this phenomenon in the regulation of a wide range of biological processes, as well as its biomedical importance.

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Section: Resultsmentioning

confidence: 99%

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

et al. 2019

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“…FBN3 encodes an extracellular matrix molecule, which has been shown to be regulated by iron in animal studies [Hill and others 2007]. Fibrillins have emerged as critical mediators of the immune response and, like other extracellular matrix proteins, may have a particular role in regulating neuroinflammation [Summers and others 2013; Zeyer and Reinhardt 2015]. The chemokine CCL25 is important for T-cell homing and antigen-specific mucosal immunity, both of which are defective in HIV and simian immunodeficiency virus (SIV) infection [Mavigner and others 2012; Qin and others 2008].…”

Section: Discussionmentioning

confidence: 99%

Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

Jia

Zhao

Hulgan

et al. 2017

American J of Med Genetics Pt B

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HIV-associated neurocognitive disorder (HAND) often complicates HIV infection despite combination antiretroviral therapy (ART) and may be influenced by host genomics. We performed a genome-wide association study (GWAS) of HAND in 1,050 CNS HIV Anti-Retroviral Therapy Effects Research (CHARTER) Study participants. All participants underwent standardized, comprehensive neurocognitive and neuromedical assessments to determine if they had cognitive impairment as assessed by the Global Deficit Score (GDS), and individuals with comorbidities that could confound diagnosis of HAND were excluded. Neurocognitive outcomes included GDS-defined neurocognitive impairment (NCI; binary GDS, 366 cases with GDS≥0.5 and 684 controls with GDS<0.5, and GDS as a continuous variable) and Frascati HAND definitions that incorporate assessment of functional impairment by self-report and performance-based criteria. Genotype data was obtained using the Affymetrix Human SNP Array 6.0 platform. Multivariable logistic or linear regression-based association tests were performed for GDS-defined NCI and HAND. GWAS results did not reveal SNPs meeting the genome-wide significance threshold (5.0×10−8) for GDS-defined NCI or HAND. For binary GDS, the most significant SNPs were rs6542826 (p=8.1×10−7) and rs11681615 (1.2×10−6), both located on chromosome 2 in SH3RF3. The most significant SNP for continuous GDS was rs11157436 (p=1.3×10−7) on chromosome 14 in the T-cell-receptor alpha locus; three other SNPs in this gene were also associated with binary GDS (p≤2.9×10−6). This GWAS, conducted among ART-era participants from a single cohort with robust neurological phenotyping, suggests roles for several biologically plausible loci in HAND that deserve further exploration.

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“…Cys-altering mutations in the EGF domains of fibrillin, the major structural constituent of extracellular microfibrils [52,53] results in connective tissue disorders such as the Marfan syndrome. The perturbation results in short or long-range structural rearrangements, and can affect the Ca 2+ binding ability of the domain, which can lead to increased susceptibility to proteolysis, retention in the endoplasmic reticulum, and delayed secretion [52]. It has been suggested that increased oxidative stress can contribute to disease progression [54].…”

Section: Redox-sensitive Structural Switches In Disease Related Pmentioning

confidence: 99%

Large-scale analysis of redox-sensitive conditionally disordered protein regions reveal their widespread nature and key roles in high-level eukaryotic processes

Erdős¹,

Mészáros²,

Reichmann

et al. 2018

Preprint

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Recently developed quantitative redox proteomic studies enable the direct identification of redox-sensing cysteine residues that regulate the functional behavior of target proteins in response to changing levels of reactive oxygen species (ROS). At the molecular level, redox regulation can directly modify the active sites of enzymes, although a growing number of examples indicate the importance of an additional underlying mechanism that involves conditionally disordered proteins. These proteins alter their functional behavior by undergoing a disorder-to-order transition in response to changing redox conditions. However, the extent to which this mechanism is used in various proteomes is currently unknown. Here, we use a recently developed sequence-based prediction tool incorporated into the IUPred2A web server to estimate redox-sensitive conditionally disordered regions on a large scale. We show that redox-sensitive conditional disorder is fairly widespread in various proteomes and that its presence strongly correlates with the expansion of specific domains in multicellular organisms that largely rely on extra stability provided by disulfide bonds or zinc ion binding. The analyses of yeast redox proteomes and human disease data further underlie the significance of this phenomenon in the regulation of a wide range of biological processes, as well as its biomedical importance.

show abstract

Engineered mutations in fibrillin-1 leading to Marfan syndrome act at the protein, cellular and organismal levels

Cited by 38 publications

References 95 publications

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

Large‐Scale Analysis of Redox‐Sensitive Conditionally Disordered Protein Regions Reveals Their Widespread Nature and Key Roles in High‐Level Eukaryotic Processes

Genome‐wide association study of HIV‐associated neurocognitive disorder (HAND): A CHARTER group study

Large-scale analysis of redox-sensitive conditionally disordered protein regions reveal their widespread nature and key roles in high-level eukaryotic processes

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