Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations

Menade, M.; Kozlov, Guennadi; Trempe, Jean‐François; Pande, Harshit; Shenker, Solomon; Wickremasinghe, Sihara; Li, Xinlu; Hojjat, Hamed; Dicaire, Marie‐Josée; Brais, Bernard; McPherson, Peter S.; Wong, Michael; Young, Jason C.; Gehring, Kalle

doi:10.1074/jbc.ra118.003939

Cited by 15 publications

(19 citation statements)

References 49 publications

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“…Sacsin is a member of the HSP40s family, and some Hsp40s may recruit an Hsp70 to a specific set of substrates 9 . The sacsin-like gene of A. millepora contained the nucleotide-binding domain of Hsp90, a J domain and a HEPN domain (higher eukaryotes and prokaryotes nucleotide-binding domain).This is consistent with the structure of human sacsin, except that human sacsin proteins have a ubiquitin domain 25 . Two divergent sequences of the sacsin-like gene may be involved in the recruitment of Hsp70 to different substrates under stressful conditions such as changes in sea water temperature.…”

Section: Discussionsupporting

confidence: 70%

Two divergent haplogroups of a sacsin-like gene in Acropora corals

Takahashi-Kariyazono

Terai

2021

Sci Rep

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Reef-building corals are declining due to environmental changes. Sacsin is a member of the heat shock proteins and has been reported as a candidate protein associated with the stress response in Acropora corals. Recently, high nucleotide diversity and the persistence of two divergent haplogroups of sacsin-like genes in Acropora millepora have been reported. While it was not clear when the two haplogroups have split and whether the haplogroups have persisted in only A. millepora or the other lineages in the genus Acropora. In this study, we analyzed a genomic region containing a sacsin-like gene from Acropora and Montipora species. Higher nucleotide diversity in the sacsin-like gene compared with that of surrounding regions was also observed in A. digitifera. This nucleotide diversity is derived from two divergent haplogroups of a sacsin-like gene, which are present in at least three Acropora species. The origin of these two haplogroups can be traced back before the divergence of Acropora and Montipora (119 Ma). Although the link between exceptionally high genetic variation in sacsin-like genes and functional differences in sacsin-like proteins is not clear, the divergent haplogroups may respond differently to envionmental stressors and serve in the adaptive phsiological ecology of these keystone species.

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Section: Discussionsupporting

confidence: 70%

Two divergent haplogroups of a sacsin-like gene in Acropora corals

Takahashi-Kariyazono

Terai

2021

Sci Rep

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“…The domain composition of sacsin has, in part, been clarified. From the N- to the C-terminus, sacsin structure consists of: an ubiquitin-like domain that binds to the proteasome; three large sacsin repeating regions that share an Hsp90-like chaperone function; an XPCB domain that interacts with the ubiquitin ligase Ube3A; a DnaJ domain binding Hsc70 (member of the Hsp70 chaperone family); and a higher eukaryote and prokaryote nucleotide-binding domain that mediates sacsin dimerization and binds to nucleotides or their analogs 11–17 . The nature and architecture of these modules suggest that sacsin is involved in protein quality control; this would be consistent with the role that other molecular chaperones are increasingly recognized to play in neurodegeneration, specifically as key mediators of: protein homeostasis (proteostasis) in the ubiquitin-proteasome system; endoplasmic reticulum-associated degradation; and different autophagic pathways, including chaperone-mediated-, micro-, and macro-autophagy, and organelle-specific processes.…”

Section: Introductionmentioning

confidence: 99%

Functional Transcriptome Analysis in ARSACS KO Cell Model Reveals a Role of Sacsin in Autophagy

Morani

Doccini

Sirica

et al. 2019

Sci Rep

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is a rare early-onset neurological disease caused by mutations in SACS , which encodes sacsin. The complex architecture of sacsin suggests that it could be a key player in cellular protein quality control system. Molecular chaperones that operate in protein folding/unfolding and assembly/disassembly patterns have been described as essential modulators of selectivity during the autophagy process. We performed RNA-sequencing analysis to generate a whole-genome molecular signature profile of sacsin knockout cells. Using data analysis of biological processes significantly disrupted due to loss of sacsin, we confirmed the presence of decreased mitochondrial function associated with increased oxidative stress, and also provided a demonstration of a defective autophagic pathway in sacsin-depleted cells. Western blotting assays revealed decreased expression of LC3 and increased levels of p62 even after treatment with the lysosomal inhibitor bafilomycin A1, indicating impairment of the autophagic flux. Moreover, we found reduced co-immunolocalization of the autophagosome marker LC3 with lysosomal and mitochondrial markers suggesting fusion inhibition of autophagic compartments and subsequent failed cargo degradation, in particular failed degradation of damaged mitochondria. Pharmacological up-regulation of autophagy restored correct autophagic flux in sacsin knockout cells. These results corroborate the hypothesis that sacsin may play a role in autophagy. Chemical manipulation of this pathway might represent a new target to alleviate clinical and pathological symptoms, delaying the processes of neurodegeneration in ARSACS.

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“…Dysfunctions of the SIRPT domain were associated with reduced or lost ATP hydrolysis. Along with the J-domain, SIRPT domains could stimulate the ATPase activity of Hsp70 [ 28 , 29 ]. The XPC-binding domain (XPCB) could bind the Ube3A ubiquitin ligase.…”

Section: Sacsin Protein Domainsmentioning

confidence: 99%

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

Bagaria

Bagyinszky

2022

IJMS

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Autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) is an early-onset neurodegenerative disease that was originally discovered in the population from the Charlevoix-Saguenay-Lac-Saint-Jean (CSLSJ) region in Quebec. Although the disease progression of ARSACS may start in early childhood, cases with later onset have also been observed. Spasticity and ataxia could be common phenotypes, and retinal optic nerve hypermyelination is detected in the majority of patients. Other symptoms, such as pes cavus, ataxia and limb deformities, are also frequently observed in affected individuals. More than 200 mutations have been discovered in the SACS gene around the world. Besides French Canadians, SACS genetics have been extensively studied in Tunisia or Japan. Recently, emerging studies discovered SACS mutations in several other countries. SACS mutations could be associated with pathogenicity either in the homozygous or compound heterozygous stages. Sacsin has been confirmed to be involved in chaperon activities, controlling the microtubule balance or cell migration. Additionally, sacsin may also play a crucial role in regulating the mitochondrial functions. Through these mechanisms, it may share common mechanisms with other neurodegenerative diseases. Further studies are needed to define the exact functions of sacsin. This review introduces the genetic mutations discovered in the SACS gene and discusses its pathomechanisms and its possible involvement in other neurodegenerative diseases.

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Structures of ubiquitin-like (Ubl) and Hsp90-like domains of sacsin provide insight into pathological mutations

Cited by 15 publications

References 49 publications

Two divergent haplogroups of a sacsin-like gene in Acropora corals

Two divergent haplogroups of a sacsin-like gene in Acropora corals

Functional Transcriptome Analysis in ARSACS KO Cell Model Reveals a Role of Sacsin in Autophagy

Genetics of Autosomal Recessive Spastic Ataxia of Charlevoix-Saguenay (ARSACS) and Role of Sacsin in Neurodegeneration

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