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Last update 08 May 2025

CRYAB x HSP

Last update 08 May 2025

Basic Info

Related Targets

CRYABHSP

Drugs associated with CRYAB x HSP

NCI-41356

Target

CRYAB

Mechanism

CRYAB inhibitors

Active Org.

Université Bourgogne Franche-Comté

Originator Org.

Université Bourgogne Franche-Comté

Active Indication

Pulmonary Fibrosis

Inactive Indication-

Drug Highest PhasePreclinical

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

CAP-1160

Target

CRYAB x HSP

Mechanism

CRYAB stimulants [+1]

Active Org.

Plex Pharmaceuticals, Inc.

Originator Org.

Plex Pharmaceuticals, Inc.

Active Indication

Cataract

Inactive Indication-

Drug Highest PhaseDiscovery

First Approval Ctry. / Loc.-

First Approval Date20 Jan 1800

100 Clinical Results associated with CRYAB x HSP

100 Translational Medicine associated with CRYAB x HSP

0 Patents (Medical) associated with CRYAB x HSP

1,656

Literatures (Medical) associated with CRYAB x HSP

01 Jul 2025·Archives of Biochemistry and Biophysics

The p.K90N mutation in human HSPB5 highlights the critical role of lysine 90 in chaperone function and structural integrity

Article

Author: Moosavi-Movahedi, Ali Akbar ; Yousefi, Reza ; Stroylova, Yulia Y ; Saboury, Ali Akbar ; Somee, Leila Rezaei ; Amanlou, Massoud ; Shahsavani, Mohammad Bagher ; Mirzaei, Zahra ; Habibi-Rezaei, Mehran ; Muronetz, Vladimir I ; Ghaffari, Ahmad Reza ; Barinova, Ksenia V

HSPB5 (αB-crystallin), a small heat shock protein, stabilizes proteins and prevents misfolded protein aggregation through dynamic oligomer formation. Mutations in HSPB5 can result in diseases such as myopathy and cataracts. This study focuses on the myopathy-associated p.K90N mutation in the α-crystallin domain and its impact on the structure and function of human HSPB5. The recombinant mutated protein was expressed and purified for analysis using spectroscopy, microscopy, and molecular dynamics simulations. Our results reveal that the p.K90N mutation induces significant structural alterations, including an increase in β-sheet content and a reduction in α-helical structure compared to the wild-type protein. Molecular dynamics simulations showed an increased angle between dimers and decreased accessible surface area in the mutant protein. Additionally, the mutant exhibited a higher propensity for forming larger oligomers and amyloid fibrils, and enhanced thermal stability. These structural changes lead to reduced chaperone activity and impaired protein aggregation prevention, likely contributing to cell death and myopathy. Overall, the p.K90N mutation significantly alters the structural and functional properties of HSPB5, highlighting its pathogenic role and providing insights into disease mechanisms.

01 May 2025·International Journal of Biological Macromolecules

Structural characterization and functional analysis of human αB-crystallin with the p.R11G mutation: Insights into cataractogenesis and cardiomyopathy

Article

Author: Zarei, Issa ; Moosavi-Movahedi, Ali Akbar ; Bahrami, Zahra ; Yousefi, Reza ; Stroylova, Yulia Y ; Saboury, Ali Akbar ; Muronetz, Vladimir I ; Amanlou, Massoud ; Somee, Leila Rezaei ; Shahsavani, Mohammad Bagher ; Salehi, Atefeh ; Hemmati, Mahdi

αB-crystallin, a member of the small heat-shock protein family, functions as a molecular chaperone and plays a critical role in maintaining cellular homeostasis by preventing the aggregation of misfolded proteins in various tissues. This research investigates the structural and functional consequences of the p.R11G mutation in human αB-crystallin, which is associated with serious health issues, including cataracts, myofibrillar myopathy, and dilated cardiomyopathy. Following the introduction of this mutation through site-directed mutagenesis, the mutant protein was expressed in a prokaryotic host system and purified using ion-exchange chromatography. The structure and stability of the mutant protein were assessed using various spectroscopic techniques. Moreover, the oligomeric structure of the mutant protein was examined using dynamic light scattering and atomic force microscopy. To evaluate the chaperone activity and cytoprotective effects of the protein, UV-Vis spectroscopy and the 2,5-diphenyl-2H-tetrazolium bromide (MTT) assay were utilized. The results demonstrated that the p.R11G mutation significantly alters the protein's structure, leading to enhanced thermal and chemical stability, and formation of the larger oligomers compared to the wild-type protein. Additionally, the mutation was found to increase the protein's chaperone activity and its capacity to inhibit cancer cell death under oxidative stress conditions. Based on the results of our study, the significant changes observed in the structure and activity of human αB-crystallin due to this mutation elucidate the potential role of the mutated chaperone in cataract formation and myopathy. Further research is necessary to fully elucidate the underlying mechanisms and translate these findings into effective therapeutic interventions.

01 Apr 2025·Journal of Clinical Investigation

Phosphorylation of CRYAB induces a condensatopathy to worsen post–myocardial infarction left ventricular remodeling

Article

Author: Diwan, Aaradhya ; Javaheri, Ali ; Kumari, Minu ; Murphy, John T ; Nigro, Jessica ; Zhao, Chen ; Abdellatif, Mahmoud ; Islam, Moydul ; Covey, Douglas F ; Kovacs, Attila ; Margulies, Kenneth B ; Chang, Ryan P ; Weinheimer, Carla J ; Guan, Xumin ; Rawnsley, David R ; Diwan, Abhinav ; Sedej, Simon ; Young, Martin E ; Mani, Kartik ; Foroughi, Layla ; Ma, Xiucui ; Razani, Babak ; Navid, Walter ; Navid, Honora

Protein aggregates are emerging therapeutic targets in rare monogenic causes of cardiomyopathy and amyloid heart disease, but their role in more prevalent heart-failure syndromes remains mechanistically unexamined. We observed mislocalization of desmin and sarcomeric proteins to aggregates in human myocardium with ischemic cardiomyopathy and in mouse hearts with post-myocardial infarction ventricular remodeling, mimicking findings of autosomal-dominant cardiomyopathy induced by the R120G mutation in the cognate chaperone protein CRYAB. In both syndromes, we demonstrate increased partitioning of CRYAB phosphorylated on serine 59 to NP40-insoluble aggregate-rich biochemical fraction. While CRYAB undergoes phase separation to form condensates, the phosphomimetic mutation of serine 59 to aspartate (S59D) in CRYAB mimics R120G-CRYAB mutants with reduced condensate fluidity, formation of protein aggregates, and increased cell death. Conversely, changing serine to alanine (phosphorylation-deficient mutation) at position 59 (S59A) restored condensate fluidity and reduced both R120G-CRYAB aggregates and cell death. In mice, S59D CRYAB knockin was sufficient to induce desmin mislocalization and myocardial protein aggregates, while S59A CRYAB knockin rescued left ventricular systolic dysfunction after myocardial infarction and preserved desmin localization with reduced myocardial protein aggregates. 25-Hydroxycholesterol attenuated CRYAB serine 59 phosphorylation and rescued post-myocardial infarction adverse remodeling. Thus, targeting CRYAB phosphorylation-induced condensatopathy is an attractive strategy to counter ischemic cardiomyopathy.

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