ATP5MC3

UniProt ID: P48201
Organism: Homo sapiens
Review Status: COMPLETE
Aliases:
ATP5G3 ATPase subunit c Proteolipid P3
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Gene Description

ATP synthase F(0) complex subunit C2 is a paralog of ATP5MC1 that encodes an identical 51-amino acid mature protein forming the proton-conducting c-ring rotor of mitochondrial ATP synthase (Complex V). ATP5MC3 is one of three paralogous genes (ATP5MC1, ATP5MC2, ATP5MC3) distinguished only by different mitochondrial targeting sequences in the precursor proteins. The mature protein oligomerizes into a homooctamer (8-subunit c-ring) with each subunit adopting a hairpin conformation of two transmembrane Ξ±-helices. A conserved glutamic acid (Glu-59) serves as the proton-binding site driving directional rotation in response to proton flow through half-channels at the rotor-stator interface with subunit a (MT-ATP6). This rotation drives conformational changes in the F₁ catalytic domain, coupling the proton gradient to ATP synthesis. The three paralogous genes provide functional redundancy with potential tissue-specific expression differences. All structural and functional properties described for ATP5MC1 apply identically to ATP5MC3.

Existing Annotations Review

GO Term Evidence Action Reason
GO:0045259 proton-transporting ATP synthase complex
IBA
GO_REF:0000033 		ACCEPT
Summary: Phylogenetic inference. ATP5MC2 encodes subunit c which is universally conserved in F-type ATP synthases.
Reason: Core component of ATP synthase complex, highly conserved across species.
Supporting Evidence:
file:human/ATP5MC3/ATP5MC3-deep-research-perplexity.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 ATP synthesis function based on conserved c-subunit role.
Reason: Core biological process, conserved function in proton-driven ATP synthesis.
GO:0005743 mitochondrial inner membrane
IEA
GO_REF:0000117 		ACCEPT
Summary: Electronic inference for mitochondrial inner membrane localization. Subunit c is embedded in inner membrane.
Reason: Correct specific localization.
GO:0006811 monoatomic ion transport
IEA
GO_REF:0000043 		KEEP AS NON CORE
Summary: Broad parent term for ion transport. Proton transport is more specific.
Reason: Too general. Proton transmembrane transport (GO:1902600) is preferred.
GO:0008289 lipid binding
IEA
GO_REF:0000043 		ACCEPT
Summary: Subunit c binds cardiolipin, stabilizing c-ring and facilitating proton transfer.
Reason: Functionally important lipid binding, well-documented for c-subunits.
GO:0015078 proton transmembrane transporter activity
IEA
GO_REF:0000002 		ACCEPT
Summary: Proton transmembrane transporter activity - core molecular function of c-ring.
Reason: Core molecular function.
GO:0015986 proton motive force-driven ATP synthesis
IEA
GO_REF:0000002 		ACCEPT
Summary: Electronic inference for ATP synthesis. Core biological process.
Reason: Primary biological process function.
GO:0031966 mitochondrial membrane
IEA
GO_REF:0000044 		KEEP AS NON CORE
Summary: Broad mitochondrial membrane term. Inner membrane is more specific.
Reason: Too broad. Mitochondrial inner membrane (GO:0005743) preferred.
GO:0033177 proton-transporting two-sector ATPase complex, proton-transporting domain
IEA
GO_REF:0000002 		ACCEPT
Summary: C-ring is part of the Fβ‚€ proton-transporting domain.
Reason: Accurate specific component annotation.
GO:0045259 proton-transporting ATP synthase complex
IEA
GO_REF:0000120 		ACCEPT
Summary: Electronic inference for ATP synthase complex membership.
Reason: Core component of complex.
GO:1902600 proton transmembrane transport
IEA
GO_REF:0000120 		ACCEPT
Summary: Proton transmembrane transport via c-ring rotation.
Reason: Core biological process.
GO:0005743 mitochondrial inner membrane
NAS
PMID:26297831
Assembly of human mitochondrial ATP synthase through two sep... 		ACCEPT
Summary: PMID:26297831 describes ATP synthase assembly including c-ring intermediates in mitochondrial inner membrane.
Reason: Correct specific localization.
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 role in ATP synthesis.
Reason: Core biological process 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 c-ring as core component of ATP synthase complex.
Reason: Essential component of complex.
Supporting Evidence:
PMID:26297831
Assembly of human mitochondrial ATP synthase through two separate intermediates, F1-c-ring and b-e-g complex.
GO:0005739 mitochondrion
HTP
PMID:34800366
Quantitative high-confidence human mitochondrial proteome an... 		KEEP AS NON CORE
Summary: High-throughput proteomics confirms mitochondrial localization.
Reason: Broad localization. Inner membrane is more specific.
Supporting Evidence:
PMID:34800366
Epub 2021 Nov 19. Quantitative high-confidence human mitochondrial proteome and its dynamics in cellular context.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164832 		ACCEPT
Summary: Reactome pathway annotation confirming ATP synthase localization to mitochondrial inner membrane.
Reason: Accurate pathway-based annotation.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164834 		ACCEPT
Summary: Reactome pathway annotation confirming ATP synthase localization to mitochondrial inner membrane.
Reason: Accurate pathway-based annotation.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-164840 		ACCEPT
Summary: Reactome pathway annotation confirming ATP synthase localization to mitochondrial inner membrane.
Reason: Accurate pathway-based annotation.
GO:0005743 mitochondrial inner membrane
TAS
Reactome:R-HSA-8949580 		ACCEPT
Summary: Reactome pathway annotation confirming ATP synthase localization to mitochondrial inner membrane.
Reason: Accurate pathway-based annotation.
GO:0005515 protein binding
IPI
PMID:33753518
TMEM70 and TMEM242 help to assemble the rotor ring of human ... 		REMOVE
Summary: PMID:33753518 high-throughput study. Generic protein binding.
Reason: Non-informative generic term.
Supporting Evidence:
PMID:33753518
TMEM70 and TMEM242 help to assemble the rotor ring of human ATP synthase and interact with assembly factors for complex I.

Core Functions

Forming the proton-conducting channel by oligomerizing into an 8-subunit c-ring that rotates in response to proton flow, with glutamic acid-59 binding and releasing protons to drive directional rotation

Molecular Function:
proton transmembrane transporter 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:
  • file:human/ATP5MC3/ATP5MC3-uniprot.txt
    Forms c-ring rotor with proton-conducting half-channels. Mature protein identical to ATP5MC1 and ATP5MC2.
  • file:human/ATP5MC1/ATP5MC1-notes.md
    ATP5MC3 encodes identical mature protein to ATP5MC1/MC2. All functional properties are identical.

Binding cardiolipin to stabilize c-ring structure and facilitate proton translocation

Molecular Function:
lipid binding
Cellular Locations:
mitochondrial inner membrane
Supporting Evidence:
  • file:human/ATP5MC3/ATP5MC3-uniprot.txt
    Forms c-ring rotor with proton-conducting half-channels. Mature protein identical to ATP5MC1 and ATP5MC2.
  • file:human/ATP5MC1/ATP5MC1-notes.md
    ATP5MC3 encodes identical mature protein to ATP5MC1/MC2. All functional properties are identical.

References

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Suggested Questions for Experts

Q: How do the three paralogous genes (ATP5MC1/2/3) differ in tissue-specific expression patterns and regulatory control?

Suggested experts: Gene regulation specialists, Mitochondrial geneticists

Q: Is there functional compensation when one paralog is deleted, or do the genes have tissue-specific specialization despite encoding identical proteins?

Suggested experts: Mitochondrial biologists, Developmental geneticists

Suggested Experiments

Experiment: Perform tissue-specific expression profiling of ATP5MC1, ATP5MC2, and ATP5MC3 across human tissues using RNA-seq to identify differential expression patterns

Hypothesis: The three paralogs show tissue-specific expression differences despite encoding identical proteins

Type: transcriptomics

Experiment: Generate single, double, and triple knockout cell lines for ATP5MC1/2/3 to assess functional redundancy and compensation

Hypothesis: Paralogs provide functional redundancy but may have tissue-specific essentiality

Type: genetic manipulation

Deep Research

Cyberian

(ATP5MC3-deep-research-cyberian.md)

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Falcon

(ATP5MC3-deep-research-falcon.md)

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OpenAI

(ATP5MC3-deep-research-openai.md)

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Perplexity

(ATP5MC3-deep-research-perplexity-lite.md)

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Perplexity

(ATP5MC3-deep-research-perplexity.md)

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πŸ“š Additional Documentation

Notes

(ATP5MC3-notes.md)

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