Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy

Pereira, J.H.; McAndrew, R.P.; Sergeeva, Oksana A.; Ralston, Corie Y.; King, Jonathan; Adams, Paul D.

doi:10.1038/s41598-017-03825-3

Cited by 32 publications

(44 citation statements)

References 59 publications

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“…The H-B CCT5 is involved in cilia morphogenesis and survival of sensory neurons (Posokhova et al, 2011). Mutations in this gene may cause neurodegenerative diseases, such as spastic paraplegia and sensory neuropathy (Bouhouche et al, 2006;Pavel et al, 2016;Pereira et al, 2017). Additionally, TERT and CCT5, located in the critical region of CdCS, are associated with microcephaly and intellectual disability, reported in patients from several other studies ( Figure 2B; Cerruti Mainardi, 2006).…”

Section: Discussionmentioning

confidence: 83%

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

et al. 2020

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In this report, we present a patient with brain alterations and dysmorphic features associated with chromosome duplication seen in 4p16.3 region and chromosomal deletion in a critical region responsible for Cri-du-chat syndrome (CdCS). Chromosomal microarray analysis (CMA) revealed a 41.1 Mb duplication encompassing the band region 4p16.3-p13, and a 14.7 Mb deletion located between the bands 5p15.33 and p15.1. The patient's clinical findings overlap with previously reported cases of chromosome 4p duplication syndrome and CdCS. The patient's symptoms are notably similar to those of CdCS patients as she presented with a weak, high-pitched voice and showed a similar pathogenicity observed in the brain MRI. These contiguous gene syndromes present with distinct clinical manifestations. However, the phenotypic and cytogenetic variability in affected individuals, such as the low frequency and the large genomic regions that can be altered, make it challenging to identify candidate genes that contribute to the pathogenesis of these syndromes. Therefore, systems biology and CMA techniques were used to investigate the extent of chromosome rearrangement on critical regions in our patient's phenotype. We identified the candidate genes PPARGC1A, CTBP1, TRIO, TERT, and CCT5 that are associated with the neuropsychomotor delay, microcephaly, and neurological alterations found in our patient. Through investigating pathways that associate with essential nodes in the protein interaction network, we discovered proteins involved in cellular differentiation and proliferation, as well as proteins involved in the formation and disposition of the cytoskeleton. The combination of our cytogenomic and bioinformatic analysis provided these possible explanations for the unique clinical phenotype, which has not yet been described in scientific literature.

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Section: Discussionmentioning

confidence: 83%

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

et al. 2020

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“…The structural properties of the CCT5 subunit, wild type and mutated, were obtained starting from the structure of the crystallized protein deposited in the Protein Data Bank with accession codes 5UYZ [ 19 ]. The structure of the mutant subunit was obtained by changing amino acid residue 224 Leucine with Valine, using the package Maestro Schrödinger LLC, New York, NY, 2018, version 11.6.010.…”

Section: Methodsmentioning

confidence: 99%

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

Antona

Scalia

Giorgio

et al. 2020

IJMS

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Diseases associated with acquired or genetic defects in members of the chaperoning system (CS) are increasingly found and have been collectively termed chaperonopathies. Illustrative instances of genetic chaperonopathies involve the genes for chaperonins of Groups I (e.g., Heat shock protein 60, Hsp60) and II (e.g., Chaperonin Containing T-Complex polypeptide 1, CCT). Examples of the former are hypomyelinating leukodystrophy 4 (HLD4 or MitCHAP60) and hereditary spastic paraplegia (SPG13). A distal sensory mutilating neuropathy has been linked to a mutation [p.(His147Arg)] in subunit 5 of the CCT5 gene. Here, we describe a new possibly pathogenic variant [p.(Leu224Val)] of the same subunit but with a different phenotype. This yet undescribed disease affects a girl with early onset demyelinating neuropathy and a severe motor disability. By whole exome sequencing (WES), we identified a homozygous CCT5 c.670C>G p.(Leu224Val) variant in the CCT5 gene. In silico 3D-structure analysis and bioinformatics indicated that this variant could undergo abnormal conformation and could be pathogenic. We compared the patient’s clinical, neurophysiological and laboratory data with those from patients carrying p.(His147Arg) in the equatorial domain. Our patient presented signs and symptoms absent in the p.(His147Arg) cases. Molecular dynamics simulation and modelling showed that the Leu224Val mutation that occurs in the CCT5 intermediate domain near the apical domain induces a conformational change in the latter. Noteworthy is the striking difference between the phenotypes putatively linked to mutations in the same CCT subunit but located in different structural domains, offering a unique opportunity for elucidating their distinctive roles in health and disease

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“…However, the amount of sample can often be a limiting factor for targets in modern protein X-ray crystallography; consequently the number of solutions chosen to be tested during crystallization must be done critically. Understanding the factors involved in crystallization is an essential step to selecting a good set of solutions, and the Berkeley Screen, despite limited release, has already been a valuable alternative to the commercially available screens, providing crystals for several publications in the past few years (Pereira et al, 2017(Pereira et al, , 2016(Pereira et al, , 2014Marcos et al, 2017;Boyken et al, 2016;Fallas et al, 2016;Mills et al, 2016;Eudes et al, 2016;Helmich et al, 2016;Javidpour et al, 2014).…”

Section: Resultsmentioning

confidence: 99%

Berkeley Screen: a set of 96 solutions for general macromolecular crystallization

et al. 2017

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Using statistical analysis of the Biological Macromolecular Crystallization Database, combined with previous knowledge about crystallization reagents, a crystallization screen called the Berkeley Screen has been created. Correlating crystallization conditions and high-resolution protein structures, it is possible to better understand the influence that a particular solution has on protein crystal formation. Ions and small molecules such as buffers and precipitants used in crystallization experiments were identified in electron density maps, highlighting the role of these chemicals in protein crystal packing. The Berkeley Screen has been extensively used to crystallize target proteins from the Joint BioEnergy Institute and the Collaborative Crystallography program at the Berkeley Center for Structural Biology, contributing to several Protein Data Bank entries and related publications. The Berkeley Screen provides the crystallographic community with an efficient set of solutions for general macromolecular crystallization trials, offering a valuable alternative to the existing commercially available screens.

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Structure of the human TRiC/CCT Subunit 5 associated with hereditary sensory neuropathy

Cited by 32 publications

References 59 publications

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

Candidate Genes Associated With Neurological Findings in a Patient With Trisomy 4p16.3 and Monosomy 5p15.2

A Novel CCT5 Missense Variant Associated with Early Onset Motor Neuropathy

Berkeley Screen: a set of 96 solutions for general macromolecular crystallization

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