Although the sequence of a protein largely determines its function, proteins can adopt different folding states in response to changes in the environment, some of which may be deleterious to the ...organism. All organisms--Bacteria, Archaea and Eukarya--have evolved a protein homeostasis, or proteostasis, network comprising chaperones and folding factors, degradation components, signalling pathways and specialized compartmentalized modules that manage protein folding in response to environmental stimuli and variation. Surveying the origins of proteostasis networks reveals that they have co-evolved with the proteome to regulate the physiological state of the cell, reflecting the unique stresses that different cells or organisms experience, and that they have a key role in driving evolution by closely managing the link between the phenotype and the genotype.
More than 2000 mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) have been described that confer a range of molecular cell biological and functional phenotypes. Most of ...these mutations lead to compromised anion conductance at the apical plasma membrane of secretory epithelia and cause cystic fibrosis (CF) with variable disease severity. Based on the molecular phenotypic complexity of CFTR mutants and their susceptibility to pharmacotherapy, it has been recognized that mutations may impose combinatorial defects in CFTR channel biology. This notion led to the conclusion that the combination of pharmacotherapies addressing single defects (e.g., transcription, translation, folding, and/or gating) may show improved clinical benefit over available low-efficacy monotherapies. Indeed, recent phase 3 clinical trials combining ivacaftor (a gating potentiator) and lumacaftor (a folding corrector) have proven efficacious in CF patients harboring the most common mutation (deletion of residue F508, ΔF508, or Phe508del). This drug combination was recently approved by the U.S. Food and Drug Administration for patients homozygous for ΔF508. Emerging studies of the structural, cell biological, and functional defects caused by rare mutations provide a new framework that reveals a mixture of deficiencies in different CFTR alleles. Establishment of a set of combinatorial categories of the previously defined basic defects in CF alleles will aid the design of even more efficacious therapeutic interventions for CF patients.
Adapting Proteostasis for Disease Intervention Balch, William E; Morimoto, Richard I; Dillin, Andrew ...
Science (American Association for the Advancement of Science),
02/2008, Volume:
319, Issue:
5865
Journal Article
Peer reviewed
The protein components of eukaryotic cells face acute and chronic challenges to their integrity. Eukaryotic protein homeostasis, or proteostasis, enables healthy cell and organismal development and ...aging and protects against disease. Here, we describe the proteostasis network, a set of interacting activities that maintain the health of proteome and the organism. Deficiencies in proteostasis lead to many metabolic, oncological, neurodegenerative, and cardiovascular disorders. Small-molecule or biological proteostasis regulators that manipulate the concentration, conformation, quaternary structure, and/or the location of protein(s) have the potential to ameliorate some of the most challenging diseases of our era.
Many diseases appear to be caused by the misregulation of protein maintenance. Such diseases of protein homeostasis, or "proteostasis," include loss-of-function diseases (cystic fibrosis) and ...gain-of-toxic-function diseases (Alzheimer's, Parkinson's, and Huntington's disease). Proteostasis is maintained by the proteostasis network, which comprises pathways that control protein synthesis, folding, trafficking, aggregation, disaggregation, and degradation. The decreased ability of the proteostasis network to cope with inherited misfolding-prone proteins, aging, and/or metabolic/environmental stress appears to trigger or exacerbate proteostasis diseases. Herein, we review recent evidence supporting the principle that proteostasis is influenced both by an adjustable proteostasis network capacity and protein folding energetics, which together determine the balance between folding efficiency, misfolding, protein degradation, and aggregation. We review how small molecules can enhance proteostasis by binding to and stabilizing specific proteins (pharmacologic chaperones) or by increasing the proteostasis network capacity (proteostasis regulators). We propose that such therapeutic strategies, including combination therapies, represent a new approach for treating a range of diverse human maladies.
Functional amyloid--from bacteria to humans Fowler, Douglas M; Koulov, Atanas V; Balch, William E ...
Trends in biochemical sciences (Amsterdam. Regular ed.)
32, Issue:
5
Journal Article
Peer reviewed
Amyloid--a fibrillar, cross beta-sheet quaternary structure--was first discovered in the context of human disease and tissue damage, and was thought to always be detrimental to the host. Recent ...studies have identified amyloid fibers in bacteria, fungi, insects, invertebrates and humans that are functional. For example, human Pmel17 has important roles in the biosynthesis of the pigment melanin, and the factor XII protein of the hemostatic system is activated by amyloid. Functional amyloidogenesis in these systems requires tight regulation to avoid toxicity. A greater understanding of the diverse physiological applications of this fold has the potential to provide a fresh perspective for the treatment of amyloid diseases.
Genetic variation in human populations can result in the misfolding and aggregation of proteins, giving rise to systemic and neurodegenerative diseases that require management by proteostasis. Here, ...we define the role of GRP94, the endoplasmic reticulum Hsp90 chaperone paralog, in managing alpha-1-antitrypsin deficiency on a residue-by-residue basis using Gaussian process regression-based machine learning to profile the spatial covariance relationships that dictate protein folding arising from sequence variants in the population. Covariance analysis suggests a role for the ATPase activity of GRP94 in controlling the N- to C-terminal cooperative folding of alpha-1-antitrypsin responsible for the correction of liver aggregation and lung-disease phenotypes of alpha-1-antitrypsin deficiency. Gaussian process-based spatial covariance profiling provides a standard model built on covariant principles to evaluate the role of proteostasis components in guiding information flow from genome to proteome in response to genetic variation, potentially allowing us to intervene in the onset and progression of complex multi-system human diseases.
Amyloid is a generally insoluble, fibrous cross-beta sheet protein aggregate. The process of amyloidogenesis is associated with a variety of neurodegenerative diseases including Alzheimer, Parkinson, ...and Huntington disease. We report the discovery of an unprecedented functional mammalian amyloid structure generated by the protein Pmel17. This discovery demonstrates that amyloid is a fundamental nonpathological protein fold utilized by organisms from bacteria to humans. We have found that Pmel17 amyloid templates and accelerates the covalent polymerization of reactive small molecules into melanin-a critically important biopolymer that protects against a broad range of cytotoxic insults including UV and oxidative damage. Pmel17 amyloid also appears to play a role in mitigating the toxicity associated with melanin formation by sequestering and minimizing diffusion of highly reactive, toxic melanin precursors out of the melanosome. Intracellular Pmel17 amyloidogenesis is carefully orchestrated by the secretory pathway, utilizing membrane sequestration and proteolytic steps to protect the cell from amyloid and amyloidogenic intermediates that can be toxic. While functional and pathological amyloid share similar structural features, critical differences in packaging and kinetics of assembly enable the usage of Pmel17 amyloid for normal function. The discovery of native Pmel17 amyloid in mammals provides key insight into the molecular basis of both melanin formation and amyloid pathology, and demonstrates that native amyloid (amyloidin) may be an ancient, evolutionarily conserved protein quaternary structure underpinning diverse pathways contributing to normal cell and tissue physiology.
How information flow is coordinated for managing transit of 1/3 of the genome through endomembrane pathways by the coat complex II (COPII) system in response to human variation remains an enigma. By ...examining the interactome of the COPII cage-assembly component Sec13, we show that it is simultaneously associated with multiple protein complexes that facilitate different features of a continuous program of chromatin organization, transcription, translation, trafficking, and degradation steps that are differentially sensitive to Sec13 levels. For the trafficking step, and unlike other COPII components, reduction of Sec13 expression decreased the ubiquitination and degradation of wild-type (WT) and F508del variant cargo protein cystic fibrosis transmembrane conductance regulator (CFTR) leading to a striking increase in fold stability suggesting that the events differentiating export from degradation are critically dependent on COPII cage assembly at the ER Golgi intermediate compartment (ERGIC) associated recycling and degradation step linked to COPI exchange. Given Sec13's multiple roles in protein complex assemblies that change in response to its expression, we suggest that Sec13 serves as an unanticipated master regulator coordinating information flow from the genome to the proteome to facilitate spatial covariant features initiating and maintaining design and function of membrane architecture in response to human variation.
To understand the impact of genome sequence variation (the genotype) responsible for biological diversity and human health (the phenotype) including cystic fibrosis and Alzheimer’s disease, we ...developed a Gaussian-process-based machine learning (ML) approach, variation spatial profiling (VSP). VSP uses a sparse collection of known variants found in the population that perturb the protein fold to define unknown variant function based on the emergent general principle of spatial covariance (SCV). SCV quantitatively captures the role of proximity in genotype-to-phenotype spatial-temporal relationships. Phenotype landscapes generated through SCV provide a platform that can be used to describe the functional properties that drive sequence-to-function-to-structure design of the polypeptide fold at atomic resolution. We provide proof of principle that SCV can enable the use of population-based genomic platforms to define the origins and mechanism of action of genotype-to-phenotype transformations contributing to the health and disease of an individual.
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•We develop VSP, a Gaussian-process-based approach to interpret genomic diversity•VSP is based on spatial covariance (SCV) in the genotype-to-phenotype transformation•SCV uses population genomics to inform individualized phenotypes at atomic resolution•Phenotype landscapes generated through SCV enable high-definition medicine
Wang and Balch develop variation spatial profiling (VSP), a machine learning approach to integrate genomics and phenomics of the population to inform on the phenotype of the individual at atomic resolution. VSP is based on the principle of spatial covariance (SCV) that defines central dogma as matrices to track information flow from the genotype-to-phenotype to facilitate high-definition medicine.
Factors controlling the onset and progression of extracellular amyloid diseases remain largely unknown. Central to disease etiology is the efficiency of the endoplasmic reticulum (ER) machinery that ...targets destabilized mutant proteins for degradation and the enhanced tendency of these variants to aggregate if secreted. We demonstrate that mammalian cells secrete numerous transthyretin (TTR) disease-associated variants with wild-type efficiency in spite of compromised folding energetics. Only the most highly destabilized TTR variants are subjected to ER-associated degradation (ERAD) and then only in certain tissues, providing insight into tissue selective amyloidosis. Rather than a “quality control” standard based on wild-type stability, we find that ER-assisted folding (ERAF), based on global protein energetics, determines the extent of export. We propose that ERAF (influenced by the energetics of the protein fold, chaperone enzyme distributions, and metabolite chaperones) in competition with ERAD defines the unique secretory aptitude of each tissue.
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