Gene Ontology annotation through association of InterPro records with GO terms
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InterPro2GO mapping from the IPR043183 (DNJB2/6-like) domain assigns DNAJB8 the molecular functions Hsp70 protein binding (GO:0030544), protein-folding chaperone binding (GO:0051087), and unfolded protein binding (GO:0051082) by virtue of its conserved J-domain architecture.
Annotation inferences using phylogenetic trees
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PANTHER phylogenetic propagation transfers the conserved DNAJB chaperone functions (cytoplasm/nucleus localization, protein folding chaperone, protein-folding chaperone binding, unfolded protein binding, protein folding) across DNAJB6/B8 orthologues consistent with the experimental data for both paralogues.
Electronic Gene Ontology annotations created by ARBA machine learning models
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ARBA rule-based annotation assigns DNAJB8 cytoplasm localization, protein-folding chaperone binding, and negative regulation of inclusion body assembly based on UniProtKB family/keyword features shared with other DNAJB anti-aggregation chaperones.
Falcon deep research synthesis for DNAJB8
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DNAJB8 is a J-domain holdase chaperone that suppresses polyglutamine and other aggregation-prone substrates, with recent work separating oligomerization from substrate binding and anti-aggregation activity.
"Multiple studies place DNAJB8 among the most potent anti-aggregation DNAJBs, particularly against polyglutamine aggregation."
A DNAJB chaperone subfamily with HDAC-dependent activities suppresses toxic protein aggregation.
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DNAJB6b and DNAJB8 are superior suppressors of polyQ protein aggregation and toxicity within the Hsp70/Hsp110/Hsp40 chaperone network, identifying this DNAJB subclass as a distinct holdase activity.
"members of a subclass of the DNAJB family (particularly DNAJB6b and DNAJB8) are superior suppressors of aggregation and toxicity of disease-associated polyglutamine proteins."
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The anti-aggregation activity of DNAJB8 is largely independent of the N-terminal Hsp70-interacting J-domain and instead resides in a C-terminal serine-rich (SSF-SST) region and the C-terminal tail, which mediate substrate binding, polydisperse oligomer formation, and interaction with the histone deacetylases HDAC4, HDAC6, and SIRT2.
"The antiaggregation activity is largely independent of the N-terminal Hsp70-interacting J-domain. Rather, a C-terminal serine-rich (SSF-SST) region and the C-terminal tail are essential. The SSF-SST region is involved in substrate binding, formation of polydisperse oligomeric complexes, and interaction with histone deacetylases (HDAC4, HDAC6, SIRT2)."
The diverse members of the mammalian HSP70 machine show distinct chaperone-like activities.
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DNAJB8 falls in the holdase category of the Hsp70/DNAJ machine: chaperones that suppress polyQ aggregation (including DNAJB8) cannot stimulate luciferase refolding, and vice versa, establishing a functional dichotomy between holdase and foldase activities.
"Overexpressed chaperones that suppressed polyQ aggregation were found not to be able to stimulate luciferase refolding. Inversely, chaperones that supported luciferase refolding were poor suppressors of polyQ aggregation."
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Most human HSP70/HSPA and HSP40/DNAJ proteins, including DNAJB8, are cytosolic; this study also provides IDA evidence for DNAJB8 cytosolic and nuclear localization and IPI evidence for physical interaction with Hsp70 family members HSPA1A, HSPA1B, and HSPA6.
"Humans contain many HSP (heat-shock protein) 70/HSPA- and HSP40/DNAJ-encoding genes and most of the corresponding proteins are localized in the cytosol."
Proteomic characterization of the human sperm nucleus.
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DNAJB8 was identified by LC-MS/MS in the proteome of isolated human sperm nuclei (one of 403 proteins detected), supporting nuclear localization consistent with the testis-enriched expression of DNAJB8.
"403 different proteins have been identified from the isolated sperm nuclei."
The DNAJB6 and DNAJB8 protein chaperones prevent intracellular aggregation of polyglutamine peptides.
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Intracellular aggregation of expressed polyQ peptides is prevented by DNAJB6 and DNAJB8, but not by HSPA/Hsp70 or DNAJB1, identifying DNAJB6/B8 as a specialised holdase subset of the DNAJ family for polyQ substrates.
"we expressed polyQ peptides in cells and show that their intracellular aggregation is prevented by DNAJB6 and DNAJB8, members of the DNAJ (Hsp40) chaperone family. In contrast, HSPA/Hsp70 and DNAJB1, also members of the DNAJ chaperone family, did not prevent peptide-initiated aggregation."
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The mechanism of aggregation suppression by DNAJB6 and DNAJB8 is direct binding of the polyQ tract by the chaperone, providing a molecular basis for the holdase activity that does not require Hsp70 hand-off.
"we conclude that the mechanism of DNAJB6 and DNAJB8 is suppression of polyQ protein aggregation by directly binding the polyQ tract."
DNAJB8 oligomerization is mediated by an aromatic-rich motif that is dispensable for substrate activity.
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AFSSFN (147-152) steric-zipper motif resolved at 0.75 angstrom by MicroED as a class 6 steric zipper stabilized by aromatic interactions (F148, F151); F151 is a primary driver of full-length DNAJB8 self-assembly.
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Engineered monomeric DNAJB8 variants retain substrate binding and anti-aggregation function, demonstrating oligomerization is mechanistically separable from chaperone activity.
Regulatory inter-domain interactions influence Hsp70 recruitment to the DnaJB8 chaperone.
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Intramolecular JD-CTD interaction sequesters the J-domain surface, preventing Hsp70 interaction as a reversible regulatory switch controlling Hsp70 recruitment.
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DNAJB8-Clover forms juxtanuclear puncta in 39.2 +/- 3.1% of cells vs 0.44 +/- 0.50% for Clover control.
DNAJB chaperones suppress destabilised protein aggregation via a region distinct from that used to inhibit amyloidogenesis.
HSP DNAJB8 controls tumor-initiating ability in renal cancer stem-like cells.
DNAJB8 in small extracellular vesicles promotes oxaliplatin resistance through TP53/MDR1 pathway in colon cancer.
Development of an artificial antibody specific for HLA/peptide complex derived from cancer stem-like cell/cancer-initiating cell antigen DNAJB8.