Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization

Romano, Lisa E.L.; Aw, Wen; Hixson, Kathryn; Novoselova, Tatiana V.; Havener, Tammy M.; Howell, Stefanie; Taylor-Blake, Bonnie; Hall, Charlotte; Xing, Lei; Beri, Josh; Nethisinghe, Suran; Perna, Laura; Hatimy, Abubakar; Altadonna, Ginevra Chioccioli; Graves, Lee M.; Herring, Laura E.; Hickey, Anthony; Thalassinos, Konstantinos; Chapple, J. Paul; Wolter, Justin M.

doi:10.1016/j.celrep.2022.111580

Cited by 6 publications

(10 citation statements)

References 131 publications

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“…It also seems likely that if sacsin is an ATP-driven chaperone then its function could be regulated by interacting partners acting as cochaperones, as is the case for Hsp90 and other chaperones. More evidence for sacsin functioning in a chaperone network comes from its putative interactome which includes a chaperone cluster (Romano et al, 2022). Our hypothesis therefore suggests that sacsin acts as a central hub of chaperone activity, which could define it as a super molecular chaperone complex.…”

Section: Discussionmentioning

confidence: 84%

“…If this is the case a key challenge will be to identify sacsin's clients. One candidate group of proteins are intermediate filaments, which have been identified in a sacsin interacome (Romano et al, 2022). Moreover, significant reorganisation of the intermediate filament cytoskeleton is observed in sacsin null cells (Girard et al, 2012b;Lariviere et al, 2015;Bradshaw et al, 2016;Duncan et al, 2017;Gentil et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

“…The domain structure of sacsin provides a link to both the ubiquitin proteasome system and molecular chaperones, suggesting a potential function in protein quality control systems. Although there is some evidence supporting this (Parfitt et al, 2009;Gentil et al, 2019), the precise role of sasin is unknown and it is unclear why its loss results in a complex cellular phenotype that includes mitochondrial dysfunction (Girard et al, 2012a;Bradshaw et al, 2016;Morani et al, 2022), altered intermediate filament cytoskeleton organisation (Lariviere et al, 2015;Duncan et al, 2017;Gentil et al, 2019), altered microtubule dynamics (Francis et al, 2022) and disrupted intracellular trafficking (Romano et al, 2022).…”

Section: Introductionmentioning

confidence: 99%

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AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Perna

Castelli

Frasnetti

et al. 2023

Front. Mol. Biosci.

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The ataxia-linked protein sacsin has three regions of partial homology to Hsp90’s N-terminal ATP binding domain. Although a crystal structure for this Hsp90-like domain has been reported the precise molecular interactions required for ATP-binding and hydrolysis are unclear and it is debatable whether ATP biding is compatible with these domains. Furthermore, the Identification of a sacsin domain(s) equivalent to the middle domain of Hsp90 has been elusive. Here we present the superimposition of an AlphaFold structure of sacsin with yeast Hsp90, which provides novel insights into sacsin’s structure. We identify residues within the sacsin Hsp90-like domains that are required for ATP binding and hydrolysis, including the putative catalytic arginine residues equivalent to that of the Hsp90 middle domain. Importantly, our analysis allows comparison of the Hsp90 middle domain with corresponding sacsin regions and identifies a shorter lid segment, in the sacsin ATP-binding domains, than the one found in the N-terminal domain of Hsp90. Our results show how a realignment of residues in the lid segment of sacsin that are involved in ATP binding can better match equivalent residues seen in Hsp90, which we then corroborated using molecular dynamic simulations. We speculate, from a structural viewpoint, why some ATP competitive inhibitors of Hsp90 may not bind sacsin, while others would. Together our analysis supports the hypothesis that sacsin’s function is ATP-driven and would be consistent with it having a role as a super molecular chaperone. We propose that the SR1 regions of sacsin be renamed as HSP-NRD (Hsp90 N-Terminal Repeat Domain; residues 84-324) and the fragment immediately after as HSP-MRD (Hsp90 Middle Repeat Domain; residues 325-518).

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Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Perna

Castelli

Frasnetti

et al. 2023

Front. Mol. Biosci.

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“…It often is accompanied by ophthalmologic features including thickened, hypermyelinated retinal fibers and a thickerthan-average peripapillary retinal nerve fiber layer [2][3][4][5]. ARSACS patient-derived fibroblasts and mouse models present with altered mitochondrial network and morphology, intermediate filament bundling, dysregulated autophagic flux, and aberrant protein and organelle localization [6][7][8][9][10][11].…”

Section: Introductionmentioning

confidence: 99%

“…Recently, using STRING network analysis, sacsin was shown to interact with multiple heat-shock protein (HSP) chaperones, and to be a key element for trafficking to the plasma membrane of alpha integrins, which were sequestered into IF bundles [6]. We recently demonstrated direct interaction between IF and the sacsin J domain [21]; however, DNAJ domains typically have multiple clients [22].…”

Section: Introductionmentioning

confidence: 99%

Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis

Paré,

Cheng-Boivin,

Dabbaghizadeh

et al. 2024

Preprint

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Autosomal Recessive Spastic Ataxia of the Charlevoix Saguenay (ARSACS) is caused by loss of function mutations in theSACSgene encoding sacsin, a 520kDa protein with multiple functional domains. The goal of this study was to identify client proteins interacting with the J domain, a cochaperone domain interacting with Hsp70 chaperones, to gain insights into sacsin’s function and its disruption in experimental models of ARSACS. Pull downs from mouse brain identified Rabs and Rab-associated proteins including Rab1b, ARF5 and endophilin B2, involved in organelle trafficking. In cell and mouse models of ARSACS, higher molecular weight species of Rab1b were identified on SDS-PAGE in addition to the normal 25kDa band and Rab1was retained in the soma along with membranous organelles (i.e., ER, Golgi and ATG9 autophagic vesicles). These changes were reversed by expression of the DNAJ domain or the Ubl domain of sacsin and occurred independent of the formation of abnormal bundles of intermediate filaments, a key feature of ARSACS. Although Rab1b was associated with both Golgi and ER in bothSacs+/+andSacs-/-cells, expression of the DNAJ domain or the Ubl domain of sacsin increased Rab1b association with ER and restored normal electrophoretic mobility. Finally, subcellular distribution of another membrane protein, neuroplastin, a key receptor for synapse formation and plasticity, also was impaired, pointing to a general problem in Rab-dependent membrane trafficking in the absence of sacsin.

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J-domain proteins: From molecular mechanisms to diseases

Marszalek,

De Los Rios,

Cyr

et al. 2024

Cell Stress and Chaperones

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Multi-omic profiling reveals the ataxia protein sacsin is required for integrin trafficking and synaptic organization

Cited by 6 publications

References 131 publications

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

AlphaFold predicted structure of the Hsp90-like domains of the neurodegeneration linked protein sacsin reveals key residues for ATPase activity

Interactors of sacsin’s DNAJ domain identify function in organellar transport and membrane composition relevant to ARSACS pathogenesis

J-domain proteins: From molecular mechanisms to diseases

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