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Structure of Calcarisporiella thermophila Hsp104 Disaggregase that Antagonizes Diverse Proteotoxic Misfolding Events

 

RCC2 is a novel p53 target in suppressing metastasisHsp104 is an AAA+ protein disaggregase with powerful amyloid-remodeling activity. All nonmetazoan eukaryotes express Hsp104 while eubacteria express an Hsp104 ortholog, ClpB. However, most studies have focused on Hsp104 from Saccharomyces cerevisiae and ClpB orthologs from two eubacterial species. Thus, the natural spectrum of Hsp104/ClpB molecular architectures and protein-remodeling activities remains largely unexplored. Here, we report two structures of Hsp104 from the thermophilic fungus Calcarisporiella thermophila (CtHsp104), a 2.70Å crystal structure and 4.0Å cryo-electron microscopy structure. Both structures reveal left-handed, helical assemblies with all domains clearly resolved. We thus provide the highest resolution and most complete view of Hsp104 hexamers to date. We also establish that CtHsp104 antagonizes several toxic protein-misfolding events in vivo where S. cerevisiae Hsp104 is ineffective, including rescue of TDP-43, polyglutamine, and α-synuclein toxicity. We suggest that natural Hsp104 variation is an invaluable, untapped resource for illuminating therapeutic disaggregases for fatal neurodegenerative diseases.

Structure. 2018 Nov 21. pii: S0969-2126(18)30420-9. doi: 10.1016/j.str.2018.11.001.

https://doi.org/10.1016/j.str.2018.11.001

  Michalska K, Zhang K, March ZM, Hatzos-Skintges C, Pintilie G, Bigelow L, Castellano LM, Miles LJ, Jackrel ME, Chuang E, Jedrzejczak R, Shorter J, Chiu W, Joachimiak A

Breakthrough shines light on disease-fighting protein

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SBC offers applications for remote faculty supervised training of students in remote data collection on 19BM beamline.  SBC can provide standard protein crystals (lysozyme, thaumatin) for data collection. SBC resources for data collection, processing and structure determination will be available. The SBC staff will assist in training. This training will help the next generation of synchrotron light source users and scientists learn software and strategies for data collection, data processing, and structure determination. Please contact mficner@anl.gov for more information.

 

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Rigaku Actor Robot, with heated end effector, upgraded on 19-ID.

 

A sample-mounting robot is available for use at beamline 19-BM. The dewar accommodates ten Unipuck magazines; pins must be 18mm in length and use either SSRL or ALS bases. Experienced users may now request remote access to 19-BM when applying for beamtime.

 

 

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Current Beamline Statistics:

APS PDB Depositions from BioSync
SBC Sector 19 2017 2018 2019 TOTAL
ID BM ID BM ID BM
PDB Depositions 262 51 118 25 7 4 5453

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Publications Total
SBC-CAT Publication List: 19-ID 1644
SBC-CAT Publication List: 19-BM 56
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APS Publications Database

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Access to the Advanced Protein Characterization Facility (APCF), housing the Midwest Center for Structural Genomics (MCSG), requires successful completion of an ANL Guest/Joint Appointee application, procurement of an Argonne domain account, and currently valid requisite training for building #446 and ANL.

 

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