NUBPL (nucleotide-binding protein-like; also called IND1 homolog / huInd1) is a mitochondrial iron-sulfur cluster transfer protein of the Mrp/NBP35 family of P-loop NTPase Fe-S carrier proteins. Synthesized with an N-terminal mitochondrial transit peptide and imported into the mitochondrial matrix, it binds a single [4Fe-4S] cluster in a labile fashion via a conserved CXXC motif and acts as a dedicated assembly factor that delivers Fe-S cofactor(s) to subunits of respiratory chain Complex I (NADH:ubiquinone oxidoreductase). NUBPL is not a structural subunit of the Complex I holoenzyme; rather it is required for maturation of the peripheral (matrix) arm, and its loss leads to failure to accumulate Fe-S-containing subunits such as NDUFS1 and NDUFV1, reduced Complex I activity, remodeling of respiratory supercomplexes, and altered mitochondrial morphology. The protein also carries a Walker-A/P-loop ATP-binding motif characteristic of the family. In humans, biallelic loss-of-function variants in NUBPL cause mitochondrial complex I deficiency, nuclear type 21 (MC1DN21), a leukoencephalopathy with a distinctive MRI pattern.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
|
GO:0005739
mitochondrion
|
IBA
GO_REF:0000033 |
MARK AS OVER ANNOTATED |
Summary: Phylogenetic (IBA) localization to mitochondrion. Correct but generic relative to the experimentally supported and more specific mitochondrial matrix localization.
Reason: NUBPL is experimentally localized to mitochondrion (IDA, PMID:19752196) and more specifically to the mitochondrial matrix (Reactome TAS, ARBA IEA), consistent with a matrix-soluble assembly factor. The broad IBA "mitochondrion" call is superseded by the specific matrix annotation and is not treated as a distinct core localization.
Propagation Review
Root cause:
NO FAILURE NON CORE
Failure modes:
GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
|
|
GO:0032981
mitochondrial respiratory chain complex I assembly
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic (IBA) assignment of the core biological process. This matches the experimentally established role of NUBPL/IND1 as an assembly factor critically required for respiratory Complex I.
Reason: Independently supported by experimental IMP evidence (PMID:19752196), where huInd1 knockdown strongly decreased Complex I protein and activity. This is a core function.
Supporting Evidence:
PMID:19752196
huInd1, that is critically required for the assembly of complex I
|
|
GO:0016226
iron-sulfur cluster assembly
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic (IBA) assignment of iron-sulfur cluster assembly. NUBPL binds a [4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits, so it participates in the Fe-S maturation of the Complex I assembly pathway.
Reason: Consistent with the family (Mrp/NBP35 Fe-S carrier proteins) and with the experimentally demonstrated Fe-S delivery role toward Complex I (PMID:19752196). This is a core function, complementary to Complex I assembly.
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
|
|
GO:0051539
4 iron, 4 sulfur cluster binding
|
IBA
GO_REF:0000033 |
ACCEPT |
Summary: Phylogenetic (IBA) assignment of [4Fe-4S] cluster binding, the core molecular function. NUBPL binds one [4Fe-4S] cluster via a conserved CXXC motif.
Reason: Directly and independently supported by experimental IDA (PMID:19752196) and by the UniProt COFACTOR annotation ("Binds 1 [4Fe-4S] cluster"). This is a genuine, core MF.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Note=Binds 1 [4Fe-4S] cluster.
|
|
GO:0005524
ATP binding
|
IEA
GO_REF:0000002 |
KEEP AS NON CORE |
Summary: InterPro/keyword-based ATP binding. NUBPL is a Mrp/NBP35 P-loop NTPase with a Walker-A/P-loop motif and an annotated ATP-binding site (residues 75-82).
Reason: The ATP-binding P-loop is a real, conserved feature of the family, but nucleotide binding is ancillary to NUBPL's defining function (Fe-S cluster binding and delivery to Complex I). No experimental characterization of ATP hydrolysis by human NUBPL is available, so it is retained as a non-core feature-based annotation.
Propagation Review
Root cause:
NO FAILURE NON CORE
Failure modes:
GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
/ligand="ATP"
|
|
GO:0005739
mitochondrion
|
IEA
GO_REF:0000044 |
MARK AS OVER ANNOTATED |
Summary: UniProt Subcellular Location keyword mapping to mitochondrion. Correct but generic relative to the specific mitochondrial matrix localization.
Reason: Duplicates the experimentally supported mitochondrion localization at a broad granularity; the matrix-specific annotation is preferred as the core localization.
Propagation Review
Root cause:
NO FAILURE NON CORE
Failure modes:
GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
|
|
GO:0005759
mitochondrial matrix
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: ARBA machine-learning assignment to mitochondrial matrix. Consistent with a matrix-soluble assembly factor that acts on the peripheral (matrix) arm of Complex I and with the Reactome TAS matrix annotations.
Reason: NUBPL is a soluble mitochondrial protein imported via a cleavable transit peptide, and its Complex I substrate subunits (NDUFS1, NDUFV1) mature in the matrix. The matrix is the most specific well-supported localization.
Propagation Review
Root cause:
NO FAILURE CORE
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
|
|
GO:0016226
iron-sulfur cluster assembly
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro-based iron-sulfur cluster assembly, redundant with the IBA assignment of the same term. Core biological process for this Fe-S carrier protein.
Reason: Same conclusion as the IBA annotation of GO:0016226; supported by the [4Fe-4S] binding and delivery role toward Complex I.
Propagation Review
Root cause:
NO FAILURE CORE
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
|
|
GO:0032981
mitochondrial respiratory chain complex I assembly
|
IEA
GO_REF:0000117 |
ACCEPT |
Summary: ARBA machine-learning assignment of Complex I assembly, redundant with the IBA and IMP annotations of the same term. Core biological process.
Reason: Same core conclusion as the experimental IMP (PMID:19752196) and IBA annotations.
Propagation Review
Root cause:
NO FAILURE CORE
Supporting Evidence:
PMID:19752196
huInd1, that is critically required for the assembly of complex I
|
|
GO:0051536
iron-sulfur cluster binding
|
IEA
GO_REF:0000002 |
MARK AS OVER ANNOTATED |
Summary: InterPro-based generic iron-sulfur cluster binding. This is the parent of the specific [4Fe-4S] cluster binding (GO:0051539) that is experimentally supported.
Reason: NUBPL binds specifically a [4Fe-4S] cluster (UniProt COFACTOR; IDA PMID:19752196), which is captured by the more precise GO:0051539. The broad parent term is uninformative and redundant relative to the specific child.
Propagation Review
Root cause:
NO FAILURE NON CORE
Failure modes:
GRANULARITY MISMATCH
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Note=Binds 1 [4Fe-4S] cluster.
|
|
GO:0140663
ATP-dependent FeS chaperone activity
|
IEA
GO_REF:0000002 |
ACCEPT |
Summary: InterPro-based ATP-dependent FeS chaperone activity, defined as "binding to and delivering metal ions to a target protein, driven by ATP hydrolysis." This is the most specific molecular-function term for NUBPL's role as an Fe-S carrier that delivers its [4Fe-4S] cluster to Complex I subunits.
Reason: Matches the experimentally supported function: NUBPL binds a [4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits (PMID:19752196), and belongs to the ATP-binding Mrp/NBP35 carrier family. This captures the carrier/delivery molecular activity better than bare Fe-S binding and is retained as core.
Propagation Review
Root cause:
NO FAILURE CORE
Supporting Evidence:
PMID:19752196
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
|
|
GO:0005515
protein binding
|
IPI
PMID:32296183 A reference map of the human binary protein interactome. |
MARK AS OVER ANNOTATED |
Summary: Bare "protein binding" from the HuRI binary (Y2H) interactome, capturing NUBPL interactions with NUBP2 (Q9Y5Y2) and a KDM8/JMJD5 isoform (Q8N371-3). Uninformative as a molecular function.
Reason: GO:0005515 conveys no specific function. The high-throughput binary interactions do not establish a defined mitochondrial molecular activity for NUBPL; per policy an experimental IPI is retained but flagged as over-annotated rather than removed.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
Q8TB37; Q9Y5Y2: NUBP2; NbExp=6
|
|
GO:0005739
mitochondrion
|
IDA
GO_REF:0000052 |
ACCEPT |
Summary: Immunofluorescence-based (HPA, IDA) localization to mitochondrion. Directly supports mitochondrial localization of NUBPL.
Reason: Experimental (IDA) mitochondrial localization consistent with the UniProt subcellular location and the more specific matrix annotations. Retained; the matrix term is the finer-grained core localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
|
|
GO:0005739
mitochondrion
|
HTP
PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... |
KEEP AS NON CORE |
Summary: High-throughput (HTP) mitochondrial-proteome localization to mitochondrion from a quantitative high-confidence human mitochondrial proteome study.
Reason: Corroborating high-throughput evidence for mitochondrial localization; consistent with the IDA annotations but non-core relative to the specific matrix localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion
|
|
GO:0005759
mitochondrial matrix
|
TAS
Reactome:R-HSA-5690023 |
ACCEPT |
Summary: Reactome TAS placing NUBPL in the mitochondrial matrix, in the reaction where NUBPL binds the [4Fe-4S] cluster. Consistent with a matrix-soluble assembly factor.
Reason: Mitochondrial matrix is the specific, well-supported localization for this soluble assembly factor whose Complex I substrate subunits mature in the matrix.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
|
|
GO:0005759
mitochondrial matrix
|
TAS
Reactome:R-HSA-6788523 |
ACCEPT |
Summary: Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to Complex I subunits." Duplicate of the same matrix localization.
Reason: Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
|
|
GO:0005759
mitochondrial matrix
|
TAS
Reactome:R-HSA-6788556 |
ACCEPT |
Summary: Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to NDUFV1, V2." Duplicate of the same matrix localization.
Reason: Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
TRANSIT 1..38
|
|
GO:0005739
mitochondrion
|
IDA
PMID:19752196 Human ind1, an iron-sulfur cluster assembly factor for respi... |
ACCEPT |
Summary: Experimental (IDA) mitochondrial localization from the primary characterization of huInd1 (Sheftel et al. 2009), which established the subcellular location of NUBPL.
Reason: This is the source experimental IDA underlying the UniProt "Mitochondrion" subcellular location (ECO:0000269|PubMed:19752196). Core mitochondrial localization.
Supporting Evidence:
file:human/NUBPL/NUBPL-uniprot.txt
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19752196}
|
|
GO:0007005
mitochondrion organization
|
IMP
PMID:19752196 Human ind1, an iron-sulfur cluster assembly factor for respi... |
KEEP AS NON CORE |
Summary: IMP annotation based on the altered mitochondrial morphology observed upon huInd1 knockdown. This is a downstream, pleiotropic consequence of loss of Complex I rather than a direct core function of NUBPL.
Reason: NUBPL's direct role is Fe-S cluster binding and delivery for Complex I assembly; the "alteration of mitochondrial morphology" reported on knockdown is a secondary effect of respiratory-chain dysfunction, so this BP is retained as non-core rather than a defining function.
Supporting Evidence:
PMID:19752196
remodeling of respiratory supercomplexes, and alteration of mitochondrial morphology
|
|
GO:0032981
mitochondrial respiratory chain complex I assembly
|
IMP
PMID:19752196 Human ind1, an iron-sulfur cluster assembly factor for respi... |
ACCEPT |
Summary: Experimental (IMP) evidence that NUBPL/huInd1 is required for Complex I assembly: RNAi knockdown caused strong decreases in Complex I protein and activity. This is a core biological process.
Reason: This IMP is the primary experimental basis for NUBPL's function as a Complex I assembly factor and underlies the disease association (MC1DN21).
Supporting Evidence:
PMID:19752196
Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong decreases in complex I protein and activity levels
|
|
GO:0051539
4 iron, 4 sulfur cluster binding
|
IDA
PMID:19752196 Human ind1, an iron-sulfur cluster assembly factor for respi... |
ACCEPT |
Summary: Experimental (IDA) evidence that NUBPL/huInd1 binds an Fe-S cluster via a conserved CXXC motif. This is the core molecular function, matching the UniProt COFACTOR annotation of one [4Fe-4S] cluster.
Reason: Directly demonstrated cofactor binding; the CXXC-motif cysteines (Cys-244/Cys-247) are required for Complex I assembly, tying the [4Fe-4S] binding to function.
Supporting Evidence:
PMID:19752196
huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
|
UniProt: Q8TB37 (NUBPL_HUMAN). HGNC:20278. Gene synonym C14orf127. 319 aa precursor
with an N-terminal mitochondrial transit peptide (residues 1-38); mature chain 39-319
(PRO_0000184950) [file:human/NUBPL/NUBPL-uniprot.txt "TRANSIT 1..38 /note=\"Mitochondrion\""].
id: Q8TB37
gene_symbol: NUBPL
product_type: PROTEIN
status: INITIALIZED
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
NUBPL (nucleotide-binding protein-like; also called IND1 homolog / huInd1) is a
mitochondrial iron-sulfur cluster transfer protein of the Mrp/NBP35 family of P-loop
NTPase Fe-S carrier proteins. Synthesized with an N-terminal mitochondrial transit
peptide and imported into the mitochondrial matrix, it binds a single [4Fe-4S] cluster
in a labile fashion via a conserved CXXC motif and acts as a dedicated assembly factor
that delivers Fe-S cofactor(s) to subunits of respiratory chain Complex I
(NADH:ubiquinone oxidoreductase). NUBPL is not a structural subunit of the Complex I
holoenzyme; rather it is required for maturation of the peripheral (matrix) arm, and its
loss leads to failure to accumulate Fe-S-containing subunits such as NDUFS1 and NDUFV1,
reduced Complex I activity, remodeling of respiratory supercomplexes, and altered
mitochondrial morphology. The protein also carries a Walker-A/P-loop ATP-binding motif
characteristic of the family. In humans, biallelic loss-of-function variants in NUBPL
cause mitochondrial complex I deficiency, nuclear type 21 (MC1DN21), a
leukoencephalopathy with a distinctive MRI pattern.
alternative_products:
- name: '1'
id: Q8TB37-1
- name: '2'
id: Q8TB37-2
sequence_note: VSP_020985, VSP_008797
existing_annotations:
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Phylogenetic (IBA) localization to mitochondrion. Correct but generic relative to
the experimentally supported and more specific mitochondrial matrix localization.
action: MARK_AS_OVER_ANNOTATED
reason: >-
NUBPL is experimentally localized to mitochondrion (IDA, PMID:19752196) and more
specifically to the mitochondrial matrix (Reactome TAS, ARBA IEA), consistent with
a matrix-soluble assembly factor. The broad IBA "mitochondrion" call is superseded
by the specific matrix annotation and is not treated as a distinct core localization.
propagation_review:
root_cause: NO_FAILURE_NON_CORE
failure_modes:
- GRANULARITY_MISMATCH
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
Phylogenetic (IBA) assignment of the core biological process. This matches the
experimentally established role of NUBPL/IND1 as an assembly factor critically
required for respiratory Complex I.
action: ACCEPT
reason: >-
Independently supported by experimental IMP evidence (PMID:19752196), where huInd1
knockdown strongly decreased Complex I protein and activity. This is a core function.
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
huInd1, that is critically required for the assembly of complex I
- term:
id: GO:0016226
label: iron-sulfur cluster assembly
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
summary: >-
Phylogenetic (IBA) assignment of iron-sulfur cluster assembly. NUBPL binds a
[4Fe-4S] cluster and delivers Fe-S cofactor(s) to Complex I subunits, so it
participates in the Fe-S maturation of the Complex I assembly pathway.
action: ACCEPT
reason: >-
Consistent with the family (Mrp/NBP35 Fe-S carrier proteins) and with the
experimentally demonstrated Fe-S delivery role toward Complex I (PMID:19752196).
This is a core function, complementary to Complex I assembly.
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
id: GO:0051539
label: 4 iron, 4 sulfur cluster binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
summary: >-
Phylogenetic (IBA) assignment of [4Fe-4S] cluster binding, the core molecular
function. NUBPL binds one [4Fe-4S] cluster via a conserved CXXC motif.
action: ACCEPT
reason: >-
Directly and independently supported by experimental IDA (PMID:19752196) and by the
UniProt COFACTOR annotation ("Binds 1 [4Fe-4S] cluster"). This is a genuine, core MF.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- term:
id: GO:0005524
label: ATP binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
InterPro/keyword-based ATP binding. NUBPL is a Mrp/NBP35 P-loop NTPase with a
Walker-A/P-loop motif and an annotated ATP-binding site (residues 75-82).
action: KEEP_AS_NON_CORE
reason: >-
The ATP-binding P-loop is a real, conserved feature of the family, but nucleotide
binding is ancillary to NUBPL's defining function (Fe-S cluster binding and delivery
to Complex I). No experimental characterization of ATP hydrolysis by human NUBPL is
available, so it is retained as a non-core feature-based annotation.
propagation_review:
root_cause: NO_FAILURE_NON_CORE
failure_modes:
- GRANULARITY_MISMATCH
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: /ligand="ATP"
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IEA
original_reference_id: GO_REF:0000044
qualifier: located_in
review:
summary: >-
UniProt Subcellular Location keyword mapping to mitochondrion. Correct but generic
relative to the specific mitochondrial matrix localization.
action: MARK_AS_OVER_ANNOTATED
reason: >-
Duplicates the experimentally supported mitochondrion localization at a broad
granularity; the matrix-specific annotation is preferred as the core localization.
propagation_review:
root_cause: NO_FAILURE_NON_CORE
failure_modes:
- GRANULARITY_MISMATCH
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
id: GO:0005759
label: mitochondrial matrix
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: located_in
review:
summary: >-
ARBA machine-learning assignment to mitochondrial matrix. Consistent with a
matrix-soluble assembly factor that acts on the peripheral (matrix) arm of Complex I
and with the Reactome TAS matrix annotations.
action: ACCEPT
reason: >-
NUBPL is a soluble mitochondrial protein imported via a cleavable transit peptide,
and its Complex I substrate subunits (NDUFS1, NDUFV1) mature in the matrix. The
matrix is the most specific well-supported localization.
propagation_review:
root_cause: NO_FAILURE_CORE
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "TRANSIT 1..38"
- term:
id: GO:0016226
label: iron-sulfur cluster assembly
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: involved_in
review:
summary: >-
InterPro-based iron-sulfur cluster assembly, redundant with the IBA assignment of
the same term. Core biological process for this Fe-S carrier protein.
action: ACCEPT
reason: >-
Same conclusion as the IBA annotation of GO:0016226; supported by the [4Fe-4S]
binding and delivery role toward Complex I.
propagation_review:
root_cause: NO_FAILURE_CORE
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
summary: >-
ARBA machine-learning assignment of Complex I assembly, redundant with the IBA and
IMP annotations of the same term. Core biological process.
action: ACCEPT
reason: >-
Same core conclusion as the experimental IMP (PMID:19752196) and IBA annotations.
propagation_review:
root_cause: NO_FAILURE_CORE
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
huInd1, that is critically required for the assembly of complex I
- term:
id: GO:0051536
label: iron-sulfur cluster binding
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
InterPro-based generic iron-sulfur cluster binding. This is the parent of the
specific [4Fe-4S] cluster binding (GO:0051539) that is experimentally supported.
action: MARK_AS_OVER_ANNOTATED
reason: >-
NUBPL binds specifically a [4Fe-4S] cluster (UniProt COFACTOR; IDA PMID:19752196),
which is captured by the more precise GO:0051539. The broad parent term is
uninformative and redundant relative to the specific child.
propagation_review:
root_cause: NO_FAILURE_NON_CORE
failure_modes:
- GRANULARITY_MISMATCH
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- term:
id: GO:0140663
label: ATP-dependent FeS chaperone activity
evidence_type: IEA
original_reference_id: GO_REF:0000002
qualifier: enables
review:
summary: >-
InterPro-based ATP-dependent FeS chaperone activity, defined as "binding to and
delivering metal ions to a target protein, driven by ATP hydrolysis." This is the
most specific molecular-function term for NUBPL's role as an Fe-S carrier that
delivers its [4Fe-4S] cluster to Complex I subunits.
action: ACCEPT
reason: >-
Matches the experimentally supported function: NUBPL binds a [4Fe-4S] cluster and
delivers Fe-S cofactor(s) to Complex I subunits (PMID:19752196), and belongs to the
ATP-binding Mrp/NBP35 carrier family. This captures the carrier/delivery molecular
activity better than bare Fe-S binding and is retained as core.
propagation_review:
root_cause: NO_FAILURE_CORE
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:32296183
qualifier: enables
review:
summary: >-
Bare "protein binding" from the HuRI binary (Y2H) interactome, capturing NUBPL
interactions with NUBP2 (Q9Y5Y2) and a KDM8/JMJD5 isoform (Q8N371-3). Uninformative
as a molecular function.
action: MARK_AS_OVER_ANNOTATED
reason: >-
GO:0005515 conveys no specific function. The high-throughput binary interactions do
not establish a defined mitochondrial molecular activity for NUBPL; per policy an
experimental IPI is retained but flagged as over-annotated rather than removed.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "Q8TB37; Q9Y5Y2: NUBP2; NbExp=6"
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: >-
Immunofluorescence-based (HPA, IDA) localization to mitochondrion. Directly
supports mitochondrial localization of NUBPL.
action: ACCEPT
reason: >-
Experimental (IDA) mitochondrial localization consistent with the UniProt
subcellular location and the more specific matrix annotations. Retained; the matrix
term is the finer-grained core localization.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
id: GO:0005739
label: mitochondrion
evidence_type: HTP
original_reference_id: PMID:34800366
qualifier: located_in
review:
summary: >-
High-throughput (HTP) mitochondrial-proteome localization to mitochondrion from a
quantitative high-confidence human mitochondrial proteome study.
action: KEEP_AS_NON_CORE
reason: >-
Corroborating high-throughput evidence for mitochondrial localization; consistent
with the IDA annotations but non-core relative to the specific matrix localization.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "SUBCELLULAR LOCATION: Mitochondrion"
- term:
id: GO:0005759
label: mitochondrial matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5690023
qualifier: located_in
review:
summary: >-
Reactome TAS placing NUBPL in the mitochondrial matrix, in the reaction where NUBPL
binds the [4Fe-4S] cluster. Consistent with a matrix-soluble assembly factor.
action: ACCEPT
reason: >-
Mitochondrial matrix is the specific, well-supported localization for this soluble
assembly factor whose Complex I substrate subunits mature in the matrix.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "TRANSIT 1..38"
- term:
id: GO:0005759
label: mitochondrial matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6788523
qualifier: located_in
review:
summary: >-
Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to
Complex I subunits." Duplicate of the same matrix localization.
action: ACCEPT
reason: >-
Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "TRANSIT 1..38"
- term:
id: GO:0005759
label: mitochondrial matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6788556
qualifier: located_in
review:
summary: >-
Reactome TAS matrix localization from the reaction "NUBPL transfers 4Fe-4S to
NDUFV1, V2." Duplicate of the same matrix localization.
action: ACCEPT
reason: >-
Same well-supported matrix localization; consistent with NUBPL's Fe-S delivery role.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "TRANSIT 1..38"
- term:
id: GO:0005739
label: mitochondrion
evidence_type: IDA
original_reference_id: PMID:19752196
qualifier: located_in
review:
summary: >-
Experimental (IDA) mitochondrial localization from the primary characterization of
huInd1 (Sheftel et al. 2009), which established the subcellular location of NUBPL.
action: ACCEPT
reason: >-
This is the source experimental IDA underlying the UniProt "Mitochondrion"
subcellular location (ECO:0000269|PubMed:19752196). Core mitochondrial localization.
supported_by:
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: >-
SUBCELLULAR LOCATION: Mitochondrion {ECO:0000269|PubMed:19752196}
- term:
id: GO:0007005
label: mitochondrion organization
evidence_type: IMP
original_reference_id: PMID:19752196
qualifier: involved_in
review:
summary: >-
IMP annotation based on the altered mitochondrial morphology observed upon huInd1
knockdown. This is a downstream, pleiotropic consequence of loss of Complex I rather
than a direct core function of NUBPL.
action: KEEP_AS_NON_CORE
reason: >-
NUBPL's direct role is Fe-S cluster binding and delivery for Complex I assembly; the
"alteration of mitochondrial morphology" reported on knockdown is a secondary effect
of respiratory-chain dysfunction, so this BP is retained as non-core rather than a
defining function.
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
remodeling of respiratory supercomplexes, and alteration of mitochondrial
morphology
- term:
id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
evidence_type: IMP
original_reference_id: PMID:19752196
qualifier: involved_in
review:
summary: >-
Experimental (IMP) evidence that NUBPL/huInd1 is required for Complex I assembly:
RNAi knockdown caused strong decreases in Complex I protein and activity. This is a
core biological process.
action: ACCEPT
reason: >-
This IMP is the primary experimental basis for NUBPL's function as a Complex I
assembly factor and underlies the disease association (MC1DN21).
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
Knockdown of huInd1 in HeLa cells by RNA interference technology led to strong
decreases in complex I protein and activity levels
- term:
id: GO:0051539
label: 4 iron, 4 sulfur cluster binding
evidence_type: IDA
original_reference_id: PMID:19752196
qualifier: enables
review:
summary: >-
Experimental (IDA) evidence that NUBPL/huInd1 binds an Fe-S cluster via a conserved
CXXC motif. This is the core molecular function, matching the UniProt COFACTOR
annotation of one [4Fe-4S] cluster.
action: ACCEPT
reason: >-
Directly demonstrated cofactor binding; the CXXC-motif cysteines (Cys-244/Cys-247)
are required for Complex I assembly, tying the [4Fe-4S] binding to function.
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
core_functions:
- description: >-
Binds a single [4Fe-4S] cluster via a conserved CXXC motif and acts as an
ATP-binding Mrp/NBP35-family Fe-S carrier that delivers Fe-S cofactor(s) to
respiratory Complex I subunits during their maturation in the mitochondrial matrix.
molecular_function:
id: GO:0140663
label: ATP-dependent FeS chaperone activity
directly_involved_in:
- id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
- id: GO:0016226
label: iron-sulfur cluster assembly
locations:
- id: GO:0005759
label: mitochondrial matrix
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
a possible role in the delivery of one or more Fe/S clusters to complex I subunits
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
- description: >-
Binds a [4Fe-4S] iron-sulfur cluster, the cofactor that NUBPL carries and transfers;
the cluster is coordinated by a conserved CXXC motif (Cys-244/Cys-247) required for
Complex I assembly.
molecular_function:
id: GO:0051539
label: 4 iron, 4 sulfur cluster binding
directly_involved_in:
- id: GO:0032981
label: mitochondrial respiratory chain complex I assembly
locations:
- id: GO:0005759
label: mitochondrial matrix
supported_by:
- reference_id: PMID:19752196
supporting_text: >-
huInd1 can bind an Fe/S cluster via a conserved CXXC motif in a labile fashion
- reference_id: file:human/NUBPL/NUBPL-uniprot.txt
supporting_text: "Note=Binds 1 [4Fe-4S] cluster."
references:
- id: GO_REF:0000002
title: Gene Ontology annotation through association of InterPro records with GO
terms
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
InterPro2GO pipeline. Correctly recovers family-level MF/BP terms (ATP binding,
Fe-S binding, ATP-dependent FeS chaperone activity, Fe-S cluster assembly). The
generic parent GO:0051536 is redundant with the specific GO:0051539.
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PAN-GO/IBA pipeline; correctly recovers the core functions (4Fe-4S binding,
Complex I assembly, Fe-S cluster assembly, mitochondrial localization).
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location
vocabulary mapping, accompanied by conservative changes to GO terms applied by
UniProt
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
SubCell keyword mapping to mitochondrion; correct but generic relative to the
matrix-specific localization.
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
HPA immunofluorescence supporting mitochondrial localization (IDA).
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
ARBA machine-learning annotations for mitochondrial matrix localization and
Complex I assembly; consistent with experimental and Reactome evidence.
- id: PMID:19752196
title: Human ind1, an iron-sulfur cluster assembly factor for respiratory complex
I.
findings:
- statement: >-
huInd1 (NUBPL) is a mitochondrial P-loop NTPase critically required for the
assembly of respiratory Complex I; knockdown decreases Complex I protein and
activity and loss of peripheral-arm subunits.
reference_section_type: ABSTRACT
supporting_text: >-
huInd1, that is critically required for the assembly of complex I. huInd1 can
bind an Fe/S cluster via a conserved CXXC motif in a labile fashion.
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Primary characterization of human NUBPL/IND1. Only the abstract is cached
(full_text_available: false); all supporting_text quotes are verbatim from the
cached abstract. Establishes Fe-S binding, Complex I assembly requirement, and
mitochondrial localization (source of the UniProt ECO:0000269 annotations).
- id: PMID:32296183
title: A reference map of the human binary protein interactome.
findings:
- statement: >-
Large-scale binary (Y2H) interactome map (HuRI); the source of the NUBPL protein
binding (IPI) annotations to NUBP2 and a KDM8 isoform.
reference_section_type: ABSTRACT
supporting_text: >-
we present a human 'all-by-all' reference interactome map of human binary protein
interactions, or 'HuRI'.
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: >-
High-throughput binary interactome; supports the existence of interactions but not
a specific molecular function for NUBPL. Underlies the over-annotated bare
"protein binding" (GO:0005515) IPI rows.
- id: PMID:34800366
title: Quantitative high-confidence human mitochondrial proteome and its dynamics
in cellular context.
findings:
- statement: >-
High-confidence human mitochondrial proteome; corroborates mitochondrial
localization of NUBPL (HTP).
reference_section_type: ABSTRACT
supporting_text: >-
Quantitative high-confidence human mitochondrial proteome and its dynamics in
cellular context.
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
High-throughput mitochondrial proteome; supports mitochondrial localization but is
non-core relative to the specific matrix annotation.
- id: Reactome:R-HSA-5690023
title: NUBPL binds 4Fe-4S
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Reactome reaction describing NUBPL binding the [4Fe-4S] cofactor in the
mitochondrial matrix; consistent with UniProt COFACTOR and the primary literature.
- id: Reactome:R-HSA-6788523
title: NUBPL transfers 4Fe-4S to Complex I subunits
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Reactome reaction describing NUBPL transferring the [4Fe-4S] cluster to Complex I
subunits (NDUFS1/S2/S7/S8); supports the Fe-S delivery / Complex I assembly role.
- id: Reactome:R-HSA-6788556
title: NUBPL transfers 4Fe-4S to NDUFV1, V2
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Reactome reaction describing NUBPL transferring the [4Fe-4S] cluster to NDUFV1/V2;
supports the Fe-S delivery / Complex I assembly role.