Pharmacological Chaperones: Design and Development of New Therapeutic Strategies for the Treatment of Conformational Diseases

Convertino, Marino; Das, Jhuma; Dokholyan, Nikolay V.

doi:10.1021/acschembio.6b00195

Cited by 88 publications

(64 citation statements)

References 207 publications

(354 reference statements)

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“…The cofactor-based wild-type protein stabilization shows structural parallels to pharmacologic chaperone (PC) action on mutant proteins. PCs are small molecules developed to bind specific target proteins so that those proteins can assume their correct and functional 3D structure (38,39). A whole plethora of PCs has been developed and tested to stabilize mutant proteins underlying broad range of diseases, such as lysosomal storage disorders, cystic fibrosis, and various forms of amyloidosis.…”

Section: Discussionmentioning

confidence: 99%

Recognition of enzymes lacking bound cofactor by protein quality control

Martínez-Limón

Alriquet

Lang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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Protein biogenesis is tightly linked to protein quality control (PQC). The role of PQC machinery in recognizing faulty polypeptides is becoming increasingly understood. Molecular chaperones and cytosolic and vacuolar degradation systems collaborate to detect, repair, or hydrolyze mutant, damaged, and mislocalized proteins. On the other hand, the contribution of PQC to cofactor bindingrelated enzyme maturation remains largely unexplored, although the loading of a cofactor represents an all-or-nothing transition in regard to the enzymatic function and thus must be surveyed carefully. Combining proteomics and biochemical analysis, we demonstrate here that cells are able to detect functionally immature wild-type enzymes. We show that PQC-dedicated ubiquitin ligase C-terminal Hsp70-interacting protein (CHIP) recognizes and marks for degradation not only a mutant protein but also its wild-type variant as long as the latter remains cofactor free. A distinct structural feature, the protruding C-terminal tail, which appears in both the mutant and wild-type polypeptides, contributes to recognition by CHIP. Our data suggest that relative insufficiency of apoprotein degradation caused by cofactor shortage can increase amyloidogenesis and aggravate protein aggregation disorders.apoprotein | ubiquitin ligase | protein aggregation

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Section: Discussionmentioning

confidence: 99%

Recognition of enzymes lacking bound cofactor by protein quality control

Martínez-Limón

Alriquet

Lang

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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“…These pathological events caused by adoption of nonnative protein conformations lead to a large range of conditions recognized as conformational diseases (Convertino, Das, & Dokholyan, 2016; Kopito & Ron, 2000). In the control process of misfolded proteins, chaperones control the folding status of proteins by preventing and reversing protein aggregation together with ATP-dependent proteases (Weibezahn, Bukau, & Mogk, 2004).…”

Section: Perspectivesmentioning

confidence: 99%

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

Belli

Shimasaki

2018

Vitamins and Hormones

102

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Growth and differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15) are oocyte-secreted factors with a leading role in the control of ovarian function in female reproduction, modulating both the cell fate of the somatic granulosa cells and the quality and developmental competence of the egg. This short review aims to consolidate the molecular aspects of GDF9 and BMP15 and their integral actions in female fertility to understand particularly their effects on oocyte quality and fetal growth. The significant consequences of mutations in the GDF9 and BMP15 genes in women with dizygotic twins as well as the clinical relevance of these oocyte factors in the pathogenesis of primary ovarian insufficiency and polycystic ovary syndrome are also addressed.

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“…Numerous diseases arise due to mutations that disrupt protein folding, assembly, and subsequent trafficking to the cell surface (1), hereafter referred to as trafficking mutations. Small molecules termed pharmacological chaperones hold promise as a means of therapy for such diseases by interacting with mutant proteins and correcting their folding and trafficking defects (2)(3)(4).…”

mentioning

confidence: 99%

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations

Martin

Rex

Devaraneni

et al. 2016

Journal of Biological Chemistry

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ATP-sensitive potassium (K ATP ) channels play a key role in mediating glucose-stimulated insulin secretion by coupling metabolic signals to ␤-cell membrane potential. Loss of K ATP channel function due to mutations in ABCC8 or KCNJ11, genes encoding the sulfonylurea receptor 1 (SUR1) or the inwardly rectifying potassium channel Kir6.2, respectively, results in congenital hyperinsulinism. Many SUR1 mutations prevent trafficking of channel proteins from the endoplasmic reticulum to the cell surface. Channel inhibitors, including sulfonylureas and carbamazepine, have been shown to correct channel trafficking defects. In the present study, we identified 13 novel SUR1 mutations that cause channel trafficking defects, the majority of which are amenable to pharmacological rescue by glibenclamide and carbamazepine. By contrast, none of the mutant channels were rescued by K ATP channel openers. Cross-linking experiments showed that K ATP channel inhibitors promoted interactions between the N terminus of Kir6.2 and SUR1, whereas channel openers did not, suggesting the inhibitors enhance intersubunit interactions to overcome channel biogenesis and trafficking defects. Functional studies of rescued mutant channels indicate that most mutants rescued to the cell surface exhibited WT-like sensitivity to ATP, MgADP, and diazoxide. In intact cells, recovery of channel function upon trafficking rescue by reversible sulfonylureas or carbamazepine was facilitated by the K ATP channel opener diazoxide. Our study expands the list of K ATP channel trafficking mutations whose function can be recovered by pharmacological ligands and provides further insight into the structural mechanism by which channel inhibitors correct channel biogenesis and trafficking defects.Protein function relies on the proper folding, assembly, and trafficking to specific cellular compartments. In the case of plasma membrane proteins, such as ion channels and receptors, they must pass quality surveillance in the endoplasmic reticulum (ER) 3 to enter the secretory pathway and ultimately reach the cell surface. Numerous diseases arise due to mutations that disrupt protein folding, assembly, and subsequent trafficking to the cell surface (1), hereafter referred to as trafficking mutations. Small molecules termed pharmacological chaperones hold promise as a means of therapy for such diseases by interacting with mutant proteins and correcting their folding and trafficking defects (2-4).Congenital hyperinsulinism (HI) is a rare, life-threatening disease characterized by persistent insulin secretion despite extreme hypoglycemia (5). The most common cause of HI is loss-of-function mutations in the ABCC8 or KCNJ11 genes encoding the sulfonylurea receptor 1 (SUR1) and inwardly rectifying potassium channel Kir6.2 proteins, respectively (5-7). SUR1 and Kir6.2 form the pancreatic subtype of the ATP-sensitive K ϩ (K ATP ) channel, which plays a key role in glucosestimulated insulin secretion by coupling glucose metabolism to ␤-cell membrane excitability (7-9). SUR1 or Kir...

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Pharmacological Chaperones: Design and Development of New Therapeutic Strategies for the Treatment of Conformational Diseases

Cited by 88 publications

References 207 publications

Recognition of enzymes lacking bound cofactor by protein quality control

Recognition of enzymes lacking bound cofactor by protein quality control

Molecular Aspects and Clinical Relevance of GDF9 and BMP15 in Ovarian Function

Pharmacological Correction of Trafficking Defects in ATP-sensitive Potassium Channels Caused by Sulfonylurea Receptor 1 Mutations

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