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Kar2p is an ER-luminal Hsp70-family molecular chaperone that binds unfolded
polypeptides and supports protein folding homeostasis, ER import/translocation,
and quality control pathways including ERAD.
"Kar2p is an **Hsp70-family molecular chaperone** in the **ER lumen** that binds unfolded polypeptides and supports **protein folding homeostasis**, **ER import/translocation**, and quality control pathways including ER-associated degradation (ERAD)."
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Kar2p has the canonical Hsp70 domain architecture: an approximately 44 kDa ATPase
domain, an approximately 18 kDa peptide-binding pocket, and an approximately 10 kDa
C-terminal domain.
"Kar2p's **canonical domain architecture** is explicitly described as an Hsp70 with an approximately **44 kDa ATPase domain**, an approximately **18 kDa peptide-binding pocket**, and an approximately **10 kDa C-terminal domain**."
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During ER translocation the Sec63 luminal J-domain recruits Kar2p and stimulates
its ATPase activity; kar2 and sec63-1 mutant microsomes are defective for both
post- and cotranslational translocation in vitro.
"A mechanistic anchor is **Sec63**, a transmembrane protein whose **luminal J-domain recruits Kar2p** and **stimulates Kar2p ATPase activity**; sec63 J-domain mutants (e.g., sec63-1) are defective in Kar2p binding and accumulate untranslocated preproteins. ER microsomes from **kar2** and **sec63-1** mutants are defective for **both post- and cotranslational translocation in vitro**."
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Kar2p can act as a molecular ratchet during translocation, biasing client
movement into the ER lumen.
"Kar2p can function as a **“molecular ratchet”** during translocation, biasing client movement into the ER lumen."
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Under non-stress conditions Kar2 binds the luminal domain of Ire1 and inhibits
Ire1 self-association; upon ER stress Kar2 dissociates, enabling Ire1 oligomerization
and HAC1 splicing. Kar2 dissociation alone is not sufficient for full Ire1 activation.
"under non-stress conditions, Kar2 binds the **luminal domain of Ire1** and inhibits Ire1 self-association; upon ER stress, Kar2 dissociates, enabling Ire1 oligomerization and downstream HAC1 splicing. A key nuance emphasized in a 2023 review is that **Kar2 dissociation alone is not sufficient** for full Ire1 activation"
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Kar2/BiP is best viewed as an adjustor of Ire1 activity within a layered control
system rather than a simple on/off inhibitor or the sole activation switch.
"Kar2p/BiP should be viewed less as a simple “on/off inhibitor” and more as an **adjustor** of Ire1 activity with layered regulation"
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Kar2p binds unfolded or unassembled ER proteins and contributes to quality control,
maintaining client solubility and promoting retrotranslocation/degradation through ERAD.
"Kar2p binds unfolded or unassembled ER proteins and contributes to quality control, maintaining client solubility and promoting retrotranslocation/degradation through ERAD."
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Kar2p is ER-luminal with residency dependent on a C-terminal HDEL-type retrieval
sequence (FEHDEL for BiP/Kar2p); HDEL-dependent retrieval is required for cell growth.
"Soluble ER residents in budding yeast are commonly retained by **C-terminal HDEL-type retrieval sequences**. For Kar2p/BiP, an experimentally used retrieval motif is **FEHDEL** (i.e., HDEL as the terminal four residues). The H/KDEL tetrapeptide must occupy the final four residues to function, and **HDEL-dependent retrieval is required for cell growth** in budding yeast."
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Kar2p works with the J-domain cochaperone Sec63 and with Sls1p; Lhs1 and Sil1 are
nucleotide exchange factors/linked lumenal factors, and Scj1 is an Hsp40 cochaperone.
"Kar2p works with Sec63 (J-domain cochaperone) and Sls1p, which stimulates Sec63-mediated activation of Kar2p. Lhs1 and Sil1 are identified as nucleotide exchange factors/functionally linked ER lumenal factors for BiP/Kar2; Scj1 is an Hsp40 cochaperone."