HSPA1A conformational mutants reveal a conserved structural unit in Hsp70 proteins
The result's identifiers
Result code in IS VaVaI
<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F61388971%3A_____%2F20%3A00536736" target="_blank" >RIV/61388971:_____/20:00536736 - isvavai.cz</a>
Alternative codes found
RIV/00209805:_____/20:00078266 RIV/00216224:14740/20:00115316 RIV/00216208:11310/20:10415601
Result on the web
<a href="https://www.sciencedirect.com/science/article/pii/S0304416519302442" target="_blank" >https://www.sciencedirect.com/science/article/pii/S0304416519302442</a>
DOI - Digital Object Identifier
<a href="http://dx.doi.org/10.1016/j.bbagen.2019.129458" target="_blank" >10.1016/j.bbagen.2019.129458</a>
Alternative languages
Result language
angličtina
Original language name
HSPA1A conformational mutants reveal a conserved structural unit in Hsp70 proteins
Original language description
Background: The Hsp70 proteins maintain proteome integrity through the capacity of their nucleotide- and substrate-binding domains (NBD and SBD) to allosterically regulate substrate affinity in a nucleotide-dependent manner. Crystallographic studies showed that Hsp70 allostery relies on formation of contacts between ATP-bound NBD and an interdomain linker, accompanied by SBD subdomains docking onto distinct sites of the NBD leading to substrate release. However, the mechanics of ATP-induced SBD subdomains detachment is largely unknown.nMethods: Here, we investigated the structural and allosteric properties of human HSPA1A using hydrogen/deuterium exchange mass spectrometry, ATPase assays, surface plasmon resonance and fluorescence polarization-based substrate binding assays.nResults: Analysis of HSPA1A proteins bearing mutations at the interface of SBD subdomains close to the interdomain linker (amino acids L399, L510, 1515, and D529) revealed that this region forms a folding unit stabilizing the structure of both SBD subdomains in the nucleotide-free state. The introduced mutations modulate HSPA1A allostery as they localize to the NBD-SBD interfaces in the ATP-bound protein.nConclusions: These findings show that residues forming the hydrophobic structural unit stabilizing the SBD structure are relocated during ATP-activated detachment of the SBD subdomains to different NBD-SBD docking interfaces enabling HSPA1A allostery.nGeneral significance: Mutation-induced perturbations tuned HSPA1A sensitivity to peptide/protein substrates and to Hsp40 in a way that is common for other Hsp70 proteins. Our results provide an insight into structural rearrangements in the SBD of Hsp70 proteins and highlight HSPA1A-specific allostery features, which is a prerequisite for selective targeting in Hsp-related pathologies.
Czech name
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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OECD FORD branch
10606 - Microbiology
Result continuities
Project
Result was created during the realization of more than one project. More information in the Projects tab.
Continuities
I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace
Others
Publication year
2020
Confidentiality
S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů
Data specific for result type
Name of the periodical
Biochimica et Biophysica Acta. General Subjects
ISSN
0304-4165
e-ISSN
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Volume of the periodical
1864
Issue of the periodical within the volume
1
Country of publishing house
NL - THE KINGDOM OF THE NETHERLANDS
Number of pages
16
Pages from-to
129458
UT code for WoS article
000501643100014
EID of the result in the Scopus database
2-s2.0-85074488024