HSPA1L

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005634 nucleus	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for nuclear localization of HSPA1L based on phylogenetic inference across HSP70 family members. Cytosolic HSP70 family members are known to undergo nucleocytoplasmic shuttling. While HSPA1L is constitutively expressed rather than stress-inducible (PMID:1700760), as an HSP70 family member it retains the same domain architecture as HSPA1A enabling nuclear import. The Reactome pathway R-HSA-5082356 includes HSPA1L in a nuclear context for HSF1-mediated gene expression. The IBA is well-supported phylogenetically with evidence from multiple orthologs across species. Reason: Nuclear localization is a well-established property of cytosolic HSP70 family members. The phylogenetic inference is sound and additionally supported by the Reactome TAS annotation to nucleoplasm (R-HSA-5082356). HSPA1L retains the same domain architecture as HSPA1A enabling nuclear import.
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytoplasmic localization based on phylogenetic inference. HSPA1L is a cytosolic HSP70 family member. Hageman et al. (2011) state that "most of the corresponding proteins are localized in the cytosol" (PMID:21231916). HSPA1L has direct experimental evidence (IDA) for cytosol localization from the same study. The cytoplasm annotation is a broader parent term that is fully consistent with the more specific cytosol annotation. Reason: Cytoplasmic localization is the primary site of action for HSPA1L. This is supported by both phylogenetic inference and direct experimental evidence from Hageman et al. (2011) (PMID:21231916). Supporting Evidence: PMID:20072699 In all ATPase domains except for that of HSPA5/BiP the products of ATP hydrolysis, including inorganic phosphate, were observed.
GO:0005886 plasma membrane	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: IBA annotation for plasma membrane localization based on phylogenetic inference from multiple HSP70 orthologs. Some HSP70 family members have been detected at the plasma membrane, particularly in the context of immune signaling and antigen presentation. However, there is no direct experimental evidence for HSPA1L specifically at the plasma membrane. The IBA is phylogenetically derived and the localization may be more relevant to stress-inducible HSP70 members (HSPA1A/B) rather than the constitutively expressed HSPA1L. Reason: Plasma membrane localization has been documented for some HSP70 family members, particularly in immune and stress contexts. However, HSPA1L is constitutively expressed and primarily testis-enriched (PMID:9685725), making plasma membrane localization a peripheral rather than core aspect of its function. The phylogenetic inference is valid but this is not a primary localization for HSPA1L.
GO:0016887 ATP hydrolysis activity	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for ATP hydrolysis activity based on phylogenetic inference across HSP70 family members. HSPA1L contains a well-characterized N-terminal nucleotide-binding domain (NBD, residues 3-388) with defined ATP binding sites (UniProt P34931). The crystal structure of the HSPA1L ATPase domain has been solved in complex with ADP and phosphate at 1.80 angstrom resolution (PDB:3GDQ; PMID:20072699). UniProt describes the function as achieved "through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones" (UniProt P34931). The ATPase activity of HSP70 family members is stimulated by J-domain proteins (PMID:21231916). Reason: ATP hydrolysis is a core molecular function of HSPA1L. The crystal structure of the ATPase domain confirms the structural basis (PDB:3GDQ), and the phylogenetic inference is rock-solid across HSP70 family members. Supporting Evidence: PMID:21231916 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.
GO:0031072 heat shock protein binding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for heat shock protein binding based on phylogenetic inference. HSP70 family members interact with HSP40/DNAJ co-chaperones through J-domain interactions. Han et al. (2007) demonstrated that HDJC9 (a J-domain protein) "can interact with HSP70s and activate the ATPase activity of HSP70s, both of which are dependent on the J domain" (PMID:17182002). UniProt lists interactions with BAG4, CCDC28B, DNAJC7, and TRIM38 (UniProt P34931). Taipale et al. (2014) characterized the chaperone-cochaperone interaction network and detected HSPA1L interactions with cochaperones BAG4 and DNAJC7 (PMID:25036637). Reason: Heat shock protein binding is a core functional property of HSPA1L reflecting its interactions with J-domain co-chaperones and other HSP family members. This is well-supported by both phylogenetic inference and direct experimental evidence (IPI from PMID:17182002 and PMID:25036637). Supporting Evidence: PMID:17182002 HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s, both of which are dependent on the J domain. PMID:25036637 Chaperones are abundant cellular proteins that promote the folding and function of their substrate proteins (clients). In vivo, chaperones also associate with a large and diverse set of cofactors (cochaperones) that regulate their specificity and function.
GO:0044183 protein folding chaperone	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein folding chaperone activity based on phylogenetic inference across HSP70 family members. This is the core molecular function of HSPA1L. UniProt describes HSPA1L as a "molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides" (UniProt P34931). Hageman et al. (2011) directly tested HSPA1L chaperone activity in luciferase refolding and polyQ aggregation suppression assays (PMID:21231916). Reason: Protein folding chaperone is the primary molecular function of HSPA1L. This is supported by direct experimental evidence (PMID:21231916), UniProt functional annotation, and strong phylogenetic inference across HSP70 family members. Supporting Evidence: PMID:21231916 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. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. file:human/HSPA1L/HSPA1L-deep-research-falcon.md HSPA1L is an Hsp70-family ATP-dependent molecular chaperone, though direct HSPA1L-specific biochemical and localization evidence is more limited than for HSPA1A/HSPA1B.
GO:0005829 cytosol	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for cytosol localization based on phylogenetic inference. This is consistent with the IDA annotation from Hageman et al. (2011) who stated that "most of the corresponding proteins are localized in the cytosol" (PMID:21231916). HSPA1L is a canonical cytosolic HSP70 family member. Reason: Cytosol is the primary site of action for HSPA1L. The IBA is consistent with direct experimental evidence (IDA from PMID:21231916) and is the expected localization for a cytosolic HSP70 family member. Supporting Evidence: PMID:21231916 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.
GO:0042026 protein refolding	IBA GO_REF:0000033	ACCEPT	Summary: IBA annotation for protein refolding based on phylogenetic inference across HSP70 family members. HSPA1L has direct experimental support for refolding activity from Hageman et al. (2011), who tested its ability to refold heat-denatured luciferase (PMID:21231916). UniProt describes HSPA1L function as including "re-folding of misfolded proteins" (UniProt P34931). Reason: Protein refolding is a core biological process for HSPA1L. The IBA is fully supported by direct experimental evidence from the luciferase refolding assay (PMID:21231916) and phylogenetic conservation across HSP70 family members. Supporting Evidence: PMID:21231916 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. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
GO:0000166 nucleotide binding	IEA GO_REF:0000043	ACCEPT	Summary: IEA annotation for nucleotide binding based on UniProtKB keyword mapping (KW-0547). HSPA1L has a well-characterized nucleotide-binding domain (NBD, residues 3-388) with defined ATP binding sites at positions 14-17, 73, 204-206, 270-277, and 341-344 (UniProt P34931). The crystal structure confirms ADP and phosphate binding (PDB:3GDQ). This is a correct but very broad annotation; the more specific GO:0005524 (ATP binding) and GO:0016887 (ATP hydrolysis activity) annotations are already present. Reason: Nucleotide binding is correct for HSPA1L. While broad, IEA annotations at this level are acceptable. The annotation is consistent with the more specific ATP binding and ATP hydrolysis activity annotations and is supported by crystal structure data (PDB:3GDQ).
GO:0005524 ATP binding	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation for ATP binding based on combined automated annotation from InterPro and UniProtKB keyword mapping. HSPA1L has extensive ATP binding site annotations in UniProt (positions 14-17, 73, 204-206, 270-277, 341-344) and the crystal structure of its ATPase domain was solved in complex with ADP and phosphate at 1.80 angstrom resolution (PDB:3GDQ; PMID:20072699). ATP binding is fundamental to the chaperone cycle. Reason: ATP binding is a core molecular function of HSPA1L, essential for its chaperone cycle. The structural evidence from PDB:3GDQ directly confirms nucleotide binding in the NBD domain.
GO:0006950 response to stress	IEA GO_REF:0000117	KEEP AS NON CORE	Summary: IEA annotation for response to stress based on ARBA machine learning model. While HSP70 family members are generally associated with stress response, HSPA1L is notable for being constitutively expressed and NOT induced by heat shock, unlike HSPA1A/B (PMID:1700760). The annotation is technically not wrong since HSPA1L does function in protein quality control which is a component of the cellular stress response, but it is misleading for a constitutively expressed member. The term is also very broad. Reason: HSPA1L participates in protein quality control which broadly relates to stress response. However, HSPA1L is specifically NOT heat-shock inducible (PMID:1700760) and is constitutively expressed primarily in testis (PMID:9685725). The annotation is not wrong but is misleading as it suggests stress-inducibility. Keeping as non-core rather than removing because HSPA1L does contribute to proteostasis under stress conditions.
GO:0016887 ATP hydrolysis activity	IEA GO_REF:0000002	ACCEPT	Summary: IEA annotation for ATP hydrolysis activity based on InterPro domain mapping (IPR013126, HSP70 family). This duplicates the IBA annotation for the same GO term (GO_REF:0000033). The annotation is correct; HSPA1L has a well-characterized ATPase domain whose crystal structure has been solved (PDB:3GDQ; PMID:20072699). Reason: ATP hydrolysis is a core molecular function of HSPA1L. This IEA annotation is correctly derived from InterPro domain mapping and is consistent with the IBA annotation and structural evidence.
GO:0031072 heat shock protein binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for heat shock protein binding from ARBA machine learning model. This duplicates the IBA annotation for the same GO term. HSP70 family members interact with HSP40/DNAJ co-chaperones and other heat shock proteins. The annotation is consistent with experimental evidence from PMID:17182002 (interaction with HDJC9) and PMID:25036637 (interaction with BAG4 and DNAJC7). Reason: Heat shock protein binding is a core function of HSPA1L reflecting its co-chaperone interactions. This IEA annotation is consistent with existing IBA and IPI annotations for the same term.
GO:0031625 ubiquitin protein ligase binding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for ubiquitin protein ligase binding from ARBA machine learning model. This is consistent with the IPI annotation from PMID:24270810 showing HSPA1L interaction with PRKN (Parkin), an E3 ubiquitin ligase. Hasson et al. (2013) showed that "HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation" (PMID:24270810). Reason: Ubiquitin protein ligase binding is supported by the experimentally validated interaction between HSPA1L and PRKN/Parkin (PMID:24270810). This IEA annotation is consistent with the IPI evidence. Supporting Evidence: PMID:24270810 We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation.
GO:0042026 protein refolding	IEA GO_REF:0000117	ACCEPT	Summary: IEA annotation for protein refolding from ARBA machine learning model. This duplicates the IBA and IDA annotations for the same GO term. Protein refolding is directly demonstrated for HSPA1L by Hageman et al. (2011) in luciferase refolding assays (PMID:21231916). Reason: Protein refolding is a core biological process for HSPA1L. This IEA annotation is consistent with existing IBA and IDA annotations and direct experimental evidence from PMID:21231916.
GO:0051082 unfolded protein binding	IEA GO_REF:0000117	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IEA annotation was generated by the ARBA machine learning model (GO_REF:0000117). HSPA1L is a bona fide ATP-dependent protein folding chaperone of the HSP70 family. Its function is not merely passive binding to unfolded proteins, but rather active, ATP-driven chaperone-mediated protein folding. The correct replacement term is GO:0044183 (protein folding chaperone), which is already annotated via IBA (GO_REF:0000033). UniProt describes HSPA1L as a "molecular chaperone implicated in a wide variety of cellular processes, including protection of the proteome from stress, folding and transport of newly synthesized polypeptides" (UniProt P34931). An even more specific term, GO:0140662 (ATP-dependent protein folding chaperone), is also annotated via IEA from InterPro. Reason: GO:0051082 is now formally obsolete. The term conflates passive binding with the active chaperone function that HSP70 family members perform. HSPA1L is an ATP-dependent foldase that undergoes conformational cycling between ATP-bound (low substrate affinity) and ADP-bound (high substrate affinity) states to actively fold client proteins (UniProt P34931). The replacement term GO:0044183 (protein folding chaperone) accurately captures this molecular function. This IEA annotation is redundant with existing IBA and IEA annotations to GO:0044183 and GO:0140662 respectively. Proposed replacements: protein folding chaperone
GO:0005515 protein binding	IPI PMID:25036637 A quantitative chaperone interaction network reveals the arc...	MODIFY	Summary: IPI annotation for protein binding based on Taipale et al. (2014), a systematic characterization of the chaperone-cochaperone interaction network using mass spectrometry and LUMIER assays. The interacting partners from IntAct are BAG4 (O95429) and DNAJC7 (Q99615). BAG4 is a nucleotide exchange factor for HSP70, and DNAJC7 is a J-domain co-chaperone. These are functionally relevant chaperone-cochaperone interactions. However, GO:0005515 (protein binding) is uninformative. The more specific GO:0031072 (heat shock protein binding) is already annotated. Reason: The interaction data from Taipale et al. (2014) are valid and represent functionally meaningful chaperone-cochaperone interactions (HSPA1L with BAG4 and DNAJC7). However, GO:0005515 (protein binding) is uninformative per curation guidelines. The interactions are better captured by GO:0031072 (heat shock protein binding), which is already annotated via IBA and IPI. Proposed replacements: heat shock protein binding Supporting Evidence: PMID:25036637 We combined mass spectrometry and quantitative high-throughput LUMIER assays to systematically characterize the chaperone-cochaperone-client interaction network in human cells.
GO:0005515 protein binding	IPI PMID:27173435 An organelle-specific protein landscape identifies novel dis...	MARK AS OVER ANNOTATED	Summary: IPI annotation for protein binding based on Boldt et al. (2016), a large-scale organelle-specific protein landscape study. The interacting partner from IntAct is CCDC28B (Q9BUN5). CCDC28B is a coiled-coil domain protein associated with ciliopathies. The interaction with HSPA1L is from a high-throughput study and the functional significance of this specific interaction is unclear. GO:0005515 (protein binding) is uninformative. Reason: This annotation derives from a large-scale organelle-specific proteomics study (PMID:27173435). The interaction between HSPA1L and CCDC28B has no clear functional relevance to HSPA1L chaperone function, and may represent a transient or non-specific chaperone-client interaction captured in a high-throughput screen. GO:0005515 (protein binding) is uninformative per curation guidelines.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MODIFY	Summary: IPI annotation for protein binding based on Luck et al. (2020), a reference map of the human binary protein interactome using yeast two-hybrid and other methods. The interacting partners from IntAct are TRIM38 (O00635) and BAG4 (O95429). BAG4 is a known HSP70 nucleotide exchange factor and this interaction is functionally relevant. TRIM38 is an E3 ubiquitin ligase involved in innate immunity. UniProt also lists TRIM38 as an interactor (IntAct). GO:0005515 (protein binding) is uninformative. Reason: The BAG4 interaction is well-characterized as a functional cochaperone interaction and is better described by GO:0031072 (heat shock protein binding). The TRIM38 interaction is validated in two independent studies but GO:0005515 does not inform us about function. More specific terms for E3 ligase or cochaperone binding are preferred. Proposed replacements: heat shock protein binding
GO:0005515 protein binding	IPI PMID:40205054 Multimodal cell maps as a foundation for structural and func...	MODIFY	Summary: IPI annotation for protein binding from Schaffer et al. (2025), a multimodal cell map study. The interacting partner from IntAct is DNAJC7 (Q99615), a J-domain co-chaperone that is a known functional partner of HSP70 family members. This duplicates information already captured by the PMID:25036637 annotation. GO:0005515 (protein binding) is uninformative. Reason: The DNAJC7 interaction is functionally meaningful as a J-domain co-chaperone partner but GO:0005515 is uninformative. This interaction is better captured by GO:0031072 (heat shock protein binding) which is already annotated. Proposed replacements: heat shock protein binding
GO:0002199 zona pellucida receptor complex	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: IEA annotation for zona pellucida receptor complex transferred from mouse ortholog Hspa1l (UniProtKB:P16627) via Ensembl Compara. In mouse, HSP70 family members have been implicated in sperm-zona pellucida interactions during fertilization. Given that HSPA1L is specifically expressed in spermatids (PMID:9685725) and the mouse ortholog Hsc70t shares the same spermatid-specific expression pattern, this annotation is biologically plausible for a role in fertilization. Reason: The annotation is transferred from the mouse ortholog and is biologically plausible given HSPA1L spermatid-specific expression (PMID:9685725). However, direct experimental evidence for HSPA1L in the zona pellucida receptor complex in human is lacking. This is a specialized reproductive function rather than the core chaperone function. Supporting Evidence: PMID:9685725 The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in spermatids in mice.
GO:0044297 cell body	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: IEA annotation for cell body localization transferred from mouse ortholog Hspa1l (UniProtKB:P16627) via Ensembl Compara. The term GO:0044297 (cell body) refers to the neuronal cell body (soma). While some HSP70 family members are expressed in neurons, HSPA1L is primarily testis-enriched (PMID:9685725). The transfer from mouse ortholog may reflect neuronal expression of Hsc70t in mouse but this is not well-established for human HSPA1L. Reason: Cell body (neuronal soma) localization is likely an over-annotation for HSPA1L. While transferred from the mouse ortholog, HSPA1L is primarily enriched in testis/spermatids (PMID:9685725) and there is no specific evidence for neuronal cell body localization in human. The ortholog transfer may not be appropriate for this specific localization.
GO:0031072 heat shock protein binding	IPI PMID:17182002 HDJC9, a novel human type C DnaJ/HSP40 member interacts with...	ACCEPT	Summary: IPI annotation for heat shock protein binding based on Han et al. (2007), who characterized HDJC9 (DNAJC9, Q8WXX5), a novel J-domain protein. The study demonstrated that "HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s, both of which are dependent on the J domain" (PMID:17182002). The J-domain-dependent interaction between DNAJC9 and HSP70 (including HSPA1L) is a core functional interaction in the HSP70 chaperone machine. Reason: This is a well-characterized functional interaction between HSPA1L and a J-domain co-chaperone (DNAJC9/HDJC9). The J-domain-dependent interaction is fundamental to HSP70 chaperone function, as J-domain proteins stimulate the ATPase cycle. Heat shock protein binding accurately captures this co-chaperone interaction. Supporting Evidence: PMID:17182002 HDJC9 can interact with HSP70s and activate the ATPase activity of HSP70s, both of which are dependent on the J domain.
GO:0031625 ubiquitin protein ligase binding	IPI PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: IPI annotation for ubiquitin protein ligase binding based on Hasson et al. (2013), who identified HSPA1L as a positive regulator of PRKN (Parkin) translocation to damaged mitochondria. The interacting partner is PRKN/Parkin (O60260), an E3 ubiquitin ligase. The abstract states "HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation" (PMID:24270810). UniProt confirms the interaction and notes mutagenesis data: K73E (ATPase domain), L396D (substrate-binding domain), and deletion of the C-terminal EEVD motif (residues 638-641) all abolish rescue of PRKN translocation (UniProt P34931). Reason: The interaction between HSPA1L and PRKN/Parkin is well-characterized with supporting mutagenesis data. The binding to this E3 ubiquitin ligase is functionally significant in regulating mitochondrial quality control. This annotation is accurate and represents a validated non-chaperone interaction of HSPA1L. Supporting Evidence: PMID:24270810 We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation.
GO:1903749 positive regulation of protein localization to mitochondrion	IMP PMID:24270810 High-content genome-wide RNAi screens identify regulators of...	ACCEPT	Summary: IMP annotation for positive regulation of establishment of protein localization to mitochondrion based on Hasson et al. (2013). The study used genome-wide RNAi screens and found that HSPA1L promotes PRKN translocation to damaged mitochondria. The abstract states that "HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation" (PMID:24270810). UniProt mutagenesis data confirm that the ATPase domain (K73E), substrate-binding domain (L396D), and EEVD motif (deletion of 638-641) are all required for this function (UniProt P34931). This represents a specific biological role for HSPA1L in mitochondrial quality control. Reason: This annotation is well-supported by the genome-wide RNAi screen and subsequent validation in Hasson et al. (2013). HSPA1L positively regulates PRKN/Parkin translocation to damaged mitochondria, requiring functional ATPase, substrate-binding, and co-chaperone interaction domains. This is a validated biological role distinct from the general chaperone function. Supporting Evidence: PMID:24270810 We also discovered that HSPA1L (HSP70 family member) and BAG4 have mutually opposing roles in the regulation of parkin translocation.
GO:0005829 cytosol	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: IDA annotation for cytosol localization based on Hageman et al. (2011), who systematically characterized HSP70 family members. The study states that "most of the corresponding proteins are localized in the cytosol" (PMID:21231916). This is the primary subcellular localization for HSPA1L and is consistent with its function as a cytosolic chaperone. Reason: Cytosol is the primary localization for HSPA1L function. The IDA evidence from Hageman et al. (2011) directly supports this annotation and is consistent with the IBA annotation for the same term. Supporting Evidence: PMID:21231916 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.
GO:0042026 protein refolding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	ACCEPT	Summary: IDA annotation for protein refolding based on Hageman et al. (2011), who directly tested HSPA1L in luciferase refolding and polyQ aggregation suppression assays. The study "assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment" (PMID:21231916). This is direct experimental evidence for HSPA1L protein refolding activity. Reason: Protein refolding is directly demonstrated for HSPA1L by functional assays in Hageman et al. (2011). This is a core biological process annotation with strong direct experimental support. Supporting Evidence: PMID:21231916 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. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment.
GO:0051082 unfolded protein binding	IDA PMID:21231916 The diverse members of the mammalian HSP70 machine show dist...	MODIFY	Summary: GO:0051082 (unfolded protein binding) is now formally obsolete (go-ontology#30962). This IDA annotation is based on Hageman et al. (2011), which systematically compared the chaperone activities of mammalian HSP70 family members. The study tested HSPA1L and other HSP70 members for their ability to refold heat-denatured luciferase and suppress polyglutamine aggregation. As stated in the abstract, the authors "assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment" (PMID:21231916). These assays measure active protein folding chaperone function, not merely passive binding to unfolded substrates. HSPA1L, like other cytosolic HSP70 members, functions as an ATP-dependent foldase with a substrate-binding domain (residues 396-511) that binds client proteins and a nucleotide-binding domain (residues 3-388) that drives conformational cycling. The correct replacement is GO:0044183 (protein folding chaperone). Reason: GO:0051082 is now formally obsolete. The original annotation was made based on data from Hageman et al. (2011), who tested HSP70 family members in functional chaperone assays including luciferase refolding and polyQ aggregation suppression. These are active chaperone assays, not passive binding assays. The abstract states that "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" and describes their role in "refolding of heat-denatured luciferase" (PMID:21231916). UniProt further describes HSPA1L function as achieved "through cycles of ATP binding, ATP hydrolysis and ADP release, mediated by co-chaperones" where "the affinity for polypeptides is regulated by its nucleotide bound state" (UniProt P34931). This is protein folding chaperone activity, not passive unfolded protein binding. GO:0044183 (protein folding chaperone) is the correct replacement term and already has IBA support. Proposed replacements: protein folding chaperone Supporting Evidence: PMID:21231916 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. To test for possible functional differences and/or substrate specificity, we assessed the effect of overexpression of each of these HSPs on refolding of heat-denatured luciferase and on the suppression of aggregation of a non-foldable polyQ (polyglutamine)-expanded Huntingtin fragment. PMID:21231916 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.
GO:0072562 blood microparticle	HDA PMID:22516433 Proteomic analysis of microvesicles from plasma of healthy d...	KEEP AS NON CORE	Summary: HDA annotation for blood microparticle localization based on Bastos-Amador et al. (2012), a proteomic analysis of microvesicles from plasma of healthy donors. The study "purified microvesicles smaller than 220nm from plasma of healthy donors and performed proteomic, ultra-structural, biochemical and functional analyses" and "detected 161 microvesicle-associated proteins" (PMID:22516433). HSPA1L was identified among these proteins. This is a high-throughput proteomic detection that likely reflects the general abundance of HSP70 proteins in extracellular vesicles. Reason: Detection in blood microparticles is from a high-throughput proteomics study and likely reflects general HSP70 family presence in extracellular vesicles rather than a specific function of HSPA1L. The study noted "remarkably high variability in the protein content of plasma from different donors" (PMID:22516433), suggesting this may not be a consistent localization. Not a core localization for HSPA1L function. Supporting Evidence: PMID:22516433 In this study, we have purified microvesicles smaller than 220nm from plasma of healthy donors and performed proteomic, ultra-structural, biochemical and functional analyses. We have detected 161 microvesicle-associated proteins
GO:0005654 nucleoplasm	TAS Reactome:R-HSA-5082356	KEEP AS NON CORE	Summary: TAS annotation for nucleoplasm localization based on Reactome pathway R-HSA-5082356 (HSF1-mediated gene expression). The Reactome pathway describes HSF1-driven upregulation of heat shock genes and places HSP70 family members in the nucleoplasm in the context of heat shock response regulation. HSF1 is "best known for rapid stress-induced upregulation of certain genes related to protein folding, such as HSPA1A/HSP70" (Reactome:R-HSA-5082356). While HSPA1L is not itself heat-inducible, it is included in this Reactome pathway as an HSP70 family member. Nuclear/nucleoplasmic localization is consistent with the IBA annotation for nucleus. Reason: Nucleoplasm localization is plausible for HSP70 family members that shuttle between cytoplasm and nucleus. However, the Reactome pathway context (HSF1-mediated heat shock response) is somewhat misleading for HSPA1L since it is not heat-inducible (PMID:1700760). The nucleoplasm localization is likely a secondary site rather than the primary cytosolic localization.
GO:0008180 COP9 signalosome	IDA PMID:18850735 Characterization of the human COP9 signalosome complex using...	KEEP AS NON CORE	Summary: IDA annotation for COP9 signalosome colocalization based on Fang et al. (2008), who characterized the human CSN complex using affinity purification and mass spectrometry. HSPA1L was identified among "52 putative human CSN interacting proteins" (PMID:18850735). Note that the GOA qualifier is "colocalizes_with" rather than "part_of", indicating HSPA1L was detected in proximity to the CSN but is not a core subunit. HSP70 chaperones commonly co-purify with multi-protein complexes as transient interactors assisting in complex assembly or quality control. Reason: HSPA1L colocalization with the COP9 signalosome likely reflects its role as a chaperone transiently interacting with the complex during assembly or quality control, rather than being a functional component of the CSN. The study identified HSPA1L among 52 putative interactors using mass spectrometry (PMID:18850735). This is a peripheral observation rather than a core localization for HSPA1L. Supporting Evidence: PMID:18850735 A total of 52 putative human CSN interacting proteins were identified, most of which are reported for the first time.
GO:0006986 response to unfolded protein	TAS PMID:9685725 Genomic structure of the spermatid-specific hsp70 homolog ge...	REMOVE	Summary: TAS annotation for response to unfolded protein based on Ito et al. (1998), who characterized the genomic structure of HSPA1L and its mouse ortholog Hsc70t. The paper describes HSPA1L as a "spermatid-specific hsp70 homolog gene" and establishes its "constitutive" expression in spermatids (PMID:9685725). While HSPA1L is an HSP70 family member that functions in protein quality control, the term "response to unfolded protein" specifically implies a response to proteotoxic stress. HSPA1L is constitutively expressed, not stress-inducible, and the cited paper does not provide evidence for induction by unfolded protein stress. Reason: PMID:9685725 supports spermatid/testis expression and genomic structure, not response to unfolded protein or proteotoxic stress. HSPA1L's chaperone role is better represented by molecular chaperone/refolding annotations. Supporting Evidence: PMID:9685725 The Hsc70t gene is a Hsp70 homolog gene expressed constitutively in spermatids in mice.

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