ATP5MC1

UniProt ID: P05496
Organism: Homo sapiens
Review Status: COMPLETE
Aliases:
ATP5G1 ATP5G ATPase subunit c Proteolipid subunit 9
πŸ“ Provide Detailed Feedback

Gene Description

ATP synthase F(0) complex subunit C1 is a critical component of the mitochondrial ATP synthase (Complex V), forming the proton-conducting c-ring rotor that couples proton translocation to ATP synthesis. The protein is a small hydrophobic 51-amino acid mature polypeptide that oligomerizes into a homooctamer (8 copies arranged in a circular ring structure), with each subunit adopting a hairpin conformation of two transmembrane Ξ±-helices. The c-ring functions as the central rotor of the Fβ‚€ domain, rotating in response to proton flow through half-channels formed at the interface with the a-subunit (MT-ATP6). A conserved glutamic acid residue (Glu-59) serves as the proton-binding site whose protonation/deprotonation drives directional rotation. This mechanical rotation of the c-ring and attached central stalk drives conformational changes in the F₁ catalytic domain, powering ATP synthesis from ADP and inorganic phosphate. ATP5MC1 is one of three paralogous genes (ATP5MC1, ATP5MC2, ATP5MC3) that encode identical mature proteins distinguished only by different mitochondrial targeting sequences. Beyond its catalytic role, ATP5MC1 participates in ATP synthase oligomerization that shapes mitochondrial cristae architecture, and under stress conditions can form the mitochondrial permeability transition pore (mPTP), a calcium-regulated ion channel involved in apoptosis.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0045259 proton-transporting ATP synthase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference based on conservation of ATP synthase subunit c across species. The c-ring is universally conserved in F-type ATP synthases from bacteria to mammals.
Reason: Highly conserved component with universal presence in ATP synthase complexes across all domains of life.
Supporting Evidence:
file:human/ATP5MC1/ATP5MC1-deep-research-openai.md
See deep research file for comprehensive analysis
GO:0015986 proton motive force-driven ATP synthesis
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference of function based on conserved role in ATP synthesis across species. The proton-driven rotary mechanism is universal.
Reason: The function is conserved across all F-type ATP synthases, with ATP5MC1 orthologs performing identical roles.
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000117 		ACCEPT
Summary: Electronic inference based on UniProt annotation. ATP5MC1 is a transmembrane protein embedded in the mitochondrial inner membrane.
Reason: Correct specific localization confirmed by experimental evidence and structural studies.
GO:0006811 monoatomic ion transport
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: Electronic inference based on keyword mapping. Proton transport is a monoatomic ion transport process.
Reason: While technically correct, this is a very broad parent term. The more specific 'proton transmembrane transport' (GO:1902600) is preferred.
GO:0008289 lipid binding
IEA
GO_REF:0000043 		ACCEPT
Summary: Electronic inference of lipid binding. ATP5MC1 binds cardiolipin, a mitochondrial-specific phospholipid that stabilizes the c-ring and facilitates proton transfer.
Reason: Cardiolipin binding is well-documented for subunit c and functionally important for ATP synthase activity.
GO:0015078 proton transmembrane transporter activity
IEA
GO_REF:0000002 		ACCEPT
Summary: Electronic inference via InterPro. Subunit c has proton transmembrane transporter activity as part of the proton channel.
Reason: This is a core molecular function accurately describing the proton translocation activity.
GO:0015986 proton motive force-driven ATP synthesis
IEA
GO_REF:0000002 		ACCEPT
Summary: Electronic inference via InterPro domain. The c-subunit is essential for proton-driven ATP synthesis.
Reason: Core biological process, well-supported by domain annotation.
GO:0031966 mitochondrial membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Electronic inference for mitochondrial membrane localization. This is a broader parent term of mitochondrial inner membrane.
Reason: While correct, the more specific 'mitochondrial inner membrane' (GO:0005743) is preferred.
GO:0033177 proton-transporting two-sector ATPase complex, proton-transporting domain
IEA
GO_REF:0000002 		ACCEPT
Summary: Electronic inference via InterPro. ATP5MC1 is part of the Fβ‚€ proton-transporting domain of the two-sector ATPase complex.
Reason: Accurate specific component annotation. The c-ring is the central rotor of the Fβ‚€ domain.
GO:0045259 proton-transporting ATP synthase complex
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined automated annotation. Redundant with IBA and IDA annotations for same term.
Reason: Correct annotation though redundant with stronger evidence codes.
GO:1902600 proton transmembrane transport
IEA
GO_REF:0000120 		ACCEPT
Summary: Combined automated annotation for proton transmembrane transport. Redundant with IDA evidence.
Reason: Core biological process, though redundant with IDA annotation.
GO:0005515 protein binding
IPI
PMID:25416956
A proteome-scale map of the human interactome network. 		REMOVE
Summary: PMID:25416956 is a proteome-wide interactome study. Generic protein binding term.
Reason: Non-informative generic protein binding term from high-throughput proteome study without specific functional context.
Supporting Evidence:
PMID:25416956
A proteome-scale map of the human interactome network.
GO:0005515 protein binding
IPI
PMID:25910212
Widespread macromolecular interaction perturbations in human... 		REMOVE
Summary: PMID:25910212 examines macromolecular interactions in genetic disorders. Generic protein binding.
Reason: Non-informative generic term without specific functional context.
Supporting Evidence:
PMID:25910212
Widespread macromolecular interaction perturbations in human genetic disorders.
GO:0005515 protein binding
IPI
PMID:31515488
Extensive disruption of protein interactions by genetic vari... 		REMOVE
Summary: PMID:31515488 on genetic variants disrupting interactions. Generic protein binding.
Reason: Non-informative generic term.
Supporting Evidence:
PMID:31515488
Extensive disruption of protein interactions by genetic variants across the allele frequency spectrum in human populations.
GO:0005515 protein binding
IPI
PMID:32296183
A reference map of the human binary protein interactome. 		REMOVE
Summary: PMID:32296183 is a reference protein interactome map. Generic protein binding.
Reason: Non-informative generic term.
Supporting Evidence:
PMID:32296183
Apr 8. A reference map of the human binary protein interactome.
GO:0005743 mitochondrial inner membrane
NAS
PMID:26297831
Assembly of human mitochondrial ATP synthase through two sep... 		ACCEPT
Summary: PMID:26297831 describes assembly of ATP synthase F1-c-ring intermediate in the mitochondrial inner membrane. Subunit c localizes to and functions in the inner mitochondrial membrane.
Reason: This is the correct and specific subcellular localization. ATP5MC1 is embedded in the inner mitochondrial membrane as part of the Fβ‚€ complex.
Supporting Evidence:
PMID:26297831
Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex.
GO:0015986 proton motive force-driven ATP synthesis
NAS
PMID:26297831
Assembly of human mitochondrial ATP synthase through two sep... 		ACCEPT
Summary: PMID:26297831 on ATP synthase assembly confirms c-ring participates in proton-motive force-driven ATP synthesis as a central component of the complex.
Reason: Well-supported by assembly studies showing c-ring is essential for ATP synthase function.
Supporting Evidence:
PMID:26297831
Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex.
GO:0045259 proton-transporting ATP synthase complex
NAS
PMID:26297831
Assembly of human mitochondrial ATP synthase through two sep... 		ACCEPT
Summary: PMID:26297831 describes F1-c-ring assembly intermediate, confirming c-subunit is a core component of the ATP synthase complex.
Reason: Direct evidence from assembly studies.
Supporting Evidence:
PMID:26297831
Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex.
GO:0015986 proton motive force-driven ATP synthesis
IDA
PMID:37244256
Structure of the human ATP synthase. 		ACCEPT
Summary: PMID:37244256 provides cryo-EM structures of human ATP synthase showing how the c-ring couples proton flow to ATP synthesis. Water molecules in half-channels suggest Grotthuss mechanism for proton transfer. The c-subunit rotational substeps drive the rotary mechanism.
Reason: This is the core biological process function of ATP5MC1. High-quality structural evidence directly demonstrates coupling of proton-motive force to ATP synthesis.
Supporting Evidence:
PMID:37244256
Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism.
GO:0015252 proton channel activity
IDA
PMID:37244256
Structure of the human ATP synthase. 		ACCEPT
Summary: PMID:37244256 demonstrates that subunit c forms the proton channel. The c-ring with subunit a creates inlet and outlet half-channels through which protons flow via Grotthuss mechanism.
Reason: This is the core molecular function. Subunit c forms the rotor that, together with subunit a, creates the proton-conducting channel.
Supporting Evidence:
PMID:37244256
Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism.
GO:0045259 proton-transporting ATP synthase complex
IDA
PMID:37244256
Structure of the human ATP synthase. 		ACCEPT
Summary: PMID:37244256 structural studies confirm ATP5MC1 is an essential component of the ATP synthase complex, forming the c-ring rotor of the Fβ‚€ domain.
Reason: This is the primary cellular component. Subunit c is an integral structural and functional component of the ATP synthase complex.
Supporting Evidence:
PMID:37244256
snapshot images for three main rotational states and one substate of human ATP synthase using cryoelectron microscopy
GO:1902600 proton transmembrane transport
IDA
PMID:37244256
Structure of the human ATP synthase. 		ACCEPT
Summary: PMID:37244256 shows protons are transported through half-channels via Grotthuss mechanism, with the c-ring facilitating proton movement across the membrane.
Reason: Core biological process. Proton transmembrane transport is the primary mechanism by which ATP5MC1 functions.
Supporting Evidence:
PMID:37244256
Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism.
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		KEEP AS NON CORE
Summary: PMID:34800366 is high-throughput mitochondrial proteome study. Broad mitochondrial localization.
Reason: Correct but non-specific. The more precise 'mitochondrial inner membrane' is preferred.
Supporting Evidence:
PMID:34800366
Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0045259 proton-transporting ATP synthase complex
ISS
GO_REF:0000024 		ACCEPT
Summary: Manual transfer based on ortholog sequence similarity. ATP5MC1 orthologs are universally conserved.
Reason: Highly conserved component across species. Sequence similarity inference is valid.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164832 		ACCEPT
Summary: Reactome pathway 'ATPase synthesizes ATP' localizes ATP5MC1 to mitochondrial inner membrane.
Reason: Correct localization from curated pathway database.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164834 		ACCEPT
Summary: Reactome pathway 'Enzyme-bound ATP is released' shows ATP synthase in inner membrane.
Reason: Accurate pathway-based annotation.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164840 		ACCEPT
Summary: Reactome pathway 'ADP and Pi bind to ATPase' localizes complex to inner membrane.
Reason: Correct pathway annotation.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-8949580 		ACCEPT
Summary: Reactome pathway 'F1Fo ATP synthase dimerizes' shows dimerization occurs in inner membrane.
Reason: Accurate annotation. ATP synthase dimerization in cristae is well-documented.
GO:0005515 protein binding
IPI
PMID:33359711
TMEM70 forms oligomeric scaffolds within mitochondrial crist... 		KEEP AS NON CORE
Summary: PMID:33359711 describes TMEM70 interaction with ATP5MC1. TMEM70 facilitates c-ring assembly.
Reason: Protein binding is generic, but this represents a functionally important interaction with TMEM70 assembly factor that facilitates c-ring incorporation. More specific annotation would be ideal but generic protein binding captures the basic interaction.
Supporting Evidence:
PMID:33359711
TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel.
PMID:31652072
Oct 25. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme.
GO:0005515 protein binding
IPI
PMID:31652072
TMEM70 facilitates biogenesis of mammalian ATP synthase by p... 		KEEP AS NON CORE
Summary: PMID:31652072 demonstrates TMEM70 binding to ATP5MC1, facilitating c-ring assembly and protecting from proteolysis.
Reason: Protein binding is generic, but this represents a functionally important interaction with TMEM70 assembly factor that facilitates c-ring incorporation. More specific annotation would be ideal but generic protein binding captures the basic interaction.
Supporting Evidence:
PMID:31652072
Oct 25. TMEM70 facilitates biogenesis of mammalian ATP synthase by promoting subunit c incorporation into the rotor structure of the enzyme.
PMID:33359711
TMEM70 forms oligomeric scaffolds within mitochondrial cristae promoting in situ assembly of mammalian ATP synthase proton channel.
GO:0005739 mitochondrion
IDA
GO_REF:0000054 		KEEP AS NON CORE
Summary: Direct assay based on intracellular localization of fusion proteins. Mitochondrial localization confirmed.
Reason: Broad localization term. More specific inner membrane annotation is preferred.

Core Functions

Forming the proton-conducting channel of ATP synthase by oligomerizing into an 8-subunit c-ring that rotates in response to proton flow, with each subunit containing a critical glutamic acid (Glu-59) that binds and releases protons to drive directional rotation

Molecular Function:
proton channel activity
Directly Involved In:
proton transmembrane transport proton motive force-driven ATP synthesis
Cellular Locations:
mitochondrial inner membrane
In Complex:
proton-transporting two-sector ATPase complex, proton-transporting domain
Supporting Evidence:
  • PMID:37244256
    Water molecules are identified in the inlet and outlet half-channels, suggesting that the proton transfer in these two half-channels proceed via a Grotthus mechanism
  • file:human/ATP5MC1/ATP5MC1-uniprot.txt
    With the subunit a (MT-ATP6), forms the proton-conducting channel in the Fβ‚€ domain, that contains two crucial half-channels (inlet and outlet) that facilitate proton movement from the mitochondrial intermembrane space (IMS) into the matrix. Protons are taken up via the inlet half-channel and released through the outlet half-channel, following a Grotthuss mechanism.
  • file:human/ATP5MC1/ATP5MC1-deep-research-cyberian.md
    Each c-subunit contains a conserved glutamate residue (Glu-59 in bovine/human) located in the middle of the second transmembrane helix, positioned within the hydrophobic core of the lipid bilayer. This glutamate serves as the proton-binding site and is the key functional residue for proton translocation.

Mechanically coupling proton gradient energy to ATP synthesis by serving as the central rotor that transfers rotational energy from the Fβ‚€ domain to the F₁ catalytic domain via the central stalk, driving conformational changes in beta subunits through the binding-change mechanism

Molecular Function:
proton transmembrane transporter activity
Directly Involved In:
proton motive force-driven ATP synthesis
In Complex:
proton-transporting ATP synthase complex
Supporting Evidence:
  • PMID:37244256
    The accommodation of the symmetry mismatch between F1 and Fo motors is resolved by the torsional flexing of the entire complex, especially the Ξ³ subunit, and the rotational substep of the c subunit.
  • file:human/ATP5MC1/ATP5MC1-notes.md
    8 c-subunits per ring Γ— 1 proton per subunit = 8 protons per rotation. 3 ATP synthesized per 360Β° rotation (one at each Ξ² subunit). Stoichiometry: ~2.7 protons per ATP.
  • PMID:9242922
    The three beta-subunits of F1 exist in three distinct conformational states at any given moment open (O), loose (L), and tight (T). Rotation of the gamma-subunit, driven by the c-ring, causes sequential conformational changes in each beta-subunit.
  • file:human/ATP5MC1/ATP5MC1-deep-research-cyberian.md
    For mammalian ATP synthases with c8-rings, this yields an H+/ATP ratio of 2.67, meaning approximately 2.67 protons are required to synthesize one ATP molecule. This is among the most efficient ratios observed in nature.

Binding cardiolipin to stabilize the c-ring structure and facilitate efficient proton translocation at the rotor-stator interface

Molecular Function:
lipid binding
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • file:human/ATP5MC1/ATP5MC1-uniprot.txt
    Component of ATP synthase complex that binds cardiolipin
  • file:human/ATP5MC1/ATP5MC1-notes.md
    Cardiolipin = 20% of inner membrane phospholipids. Specific non-annular binding to c-subunit. Two cardiolipin molecules near Fβ‚€ half-channels regulate proton translocation and stabilize structure.
  • PMID:30760595
    No specific lipids or proteins other than ATP synthase dimers are required for row formation and membrane remodelling

References

Loading supporting content…

Download this section (compressed HTML)

Suggested Questions for Experts

Q: What is the precise molecular mechanism by which Lys-104 trimethylation by ATPSCKMT/FAM173B regulates c-ring assembly and stability?

Suggested experts: Mitochondrial biologists studying ATP synthase assembly, Post-translational modification researchers

Q: How does the c-ring stoichiometry (8 vs 10 vs 14 subunits) evolve across species, and what determines the optimal H⁺/ATP ratio for different metabolic contexts?

Suggested experts: Evolutionary biologists, Mitochondrial biochemists

Q: What triggers the conformational change that converts the ATP synthase c-ring from its ATP synthesis mode to the mitochondrial permeability transition pore (mPTP) configuration, and can this be therapeutically modulated?

Suggested experts: Cell death and apoptosis researchers, Mitochondrial pathophysiologists

Q: How do the three paralogous genes (ATP5MC1/2/3) differ in tissue-specific expression regulation and assembly efficiency, and is there functional redundancy or specialization?

Suggested experts: Gene regulation specialists, Mitochondrial geneticists

Suggested Experiments

Experiment: Use cryo-EM with time-resolved imaging to capture intermediate rotational states of the c-ring during active proton translocation, correlating protonation states of Glu-59 with structural conformations

Hypothesis: Protonation of Glu-59 induces local conformational changes that propagate to drive stepwise rotation of the entire c-ring

Type: structural analysis

Experiment: Generate CRISPR knockin mice with defined c-ring stoichiometries (8 vs 10 subunits) and measure ATP synthesis efficiency, proton-to-ATP ratios, and metabolic capacity under different physiological demands

Hypothesis: C-ring stoichiometry directly determines bioenergetic efficiency and optimal function varies by tissue metabolic demands

Type: genetic manipulation

Experiment: Perform site-directed mutagenesis of Lys-104 to prevent methylation and assess effects on c-ring assembly kinetics, ATP synthase stability, and mitochondrial respiration using BN-PAGE and oxygen consumption assays

Hypothesis: Lys-104 trimethylation is essential for proper c-ring oligomerization and prevents premature proteolysis

Type: biochemical assay

Experiment: Use calcium imaging combined with patch-clamp electrophysiology to characterize the transition from ATP synthase to mPTP mode, identifying the calcium threshold and kinetics of channel opening in isolated mitochondria

Hypothesis: mPTP formation requires F₁ domain dissociation and is regulated by calcium-dependent conformational changes in the c-ring

Type: electrophysiology

Experiment: Employ proximity labeling (BioID or APEX) on ATP5MC1 to identify the complete interactome during different assembly stages and correlate with TMEM70-dependent assembly intermediates

Hypothesis: ATP5MC1 interacts with distinct assembly factors and chaperones at different stages of c-ring formation

Type: interactomics

Deep Research

Cyberian

(ATP5MC1-deep-research-cyberian.md)

Loading supporting content…

Download this section (compressed HTML)

Falcon

(ATP5MC1-deep-research-falcon.md)

Loading supporting content…

Download this section (compressed HTML)

OpenAI

(ATP5MC1-deep-research-openai.md)

Loading supporting content…

Download this section (compressed HTML)

Perplexity

(ATP5MC1-deep-research-perplexity-lite.md)

Loading supporting content…

Download this section (compressed HTML)

Perplexity

(ATP5MC1-deep-research-perplexity.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“š Additional Documentation

Notes

(ATP5MC1-notes.md)

Loading supporting content…

Download this section (compressed HTML)

πŸ“„ View Raw YAML

Loading supporting content…

Download this section (compressed HTML)