Neonatal Fc receptor (FCGRT/B2M) pH-dependent IgG and albumin salvage and transcytosis — endocytic uptake, V-ATPase acidification, FcRn acidic capture, EHD1/SNAP23 exocytic recycling vs. RAB7A/CTSD lysosomal catabolism

Immunoglobulin G (IgG) antibodies, Fc-fusion biologics, and serum albumin (ALB) achieve their exceptionally long (~19-21 day) circulatory half-lives in humans through pH-dependent endosomal salvage mediated by the heterodimeric neonatal Fc receptor (FcRn), composed of the MHC class I-like alpha chain FCGRT (p51) and beta-2-microglobulin (B2M). Vascular endothelial cells, myeloid cells, and polarized barrier epithelia continuously internalize extracellular albumin and IgG from plasma into nascent endocytic vesicles via fluid-phase pinocytosis and clathrin/AP-2/DNM2-coated pits. At neutral extracellular pH (7.4), FcRn displays negligible affinity for IgG or albumin. Once V-ATPase (ATP6V1A) acidifies early sorting endosomes to pH ~6.0-5.5, protonation of surface histidine residues on the IgG CH2-CH3 interface and albumin domain III triggers high-affinity, non-cooperative 2:1:1 binding to endosomal FCGRT/B2M heterodimers. FcRn-bound cargo is sorted away from the degradative multivesicular body pathway into EHD1-dependent recycling tubules that dock and fuse with the plasma membrane via the target-SNARE SNAP23; exposure to neutral extracellular pH (7.4) immediately deprotonates the histidine switch and releases intact IgG and albumin back into circulation (or across polarized mucosal/placental barriers). Cargo that fails to engage FcRn (or is displaced by FcRn-blocking therapeutics such as efgartigimod or by FCGRT/B2M deficiency) remains in the endosomal lumen and progresses via ESCRT-I (TSG101) and RAB7A to lysosomes for proteolytic catabolism by cathepsin D (CTSD).

MODULE:fcrn_igg_albumin_salvage_transcytosisDRAFTTransport Stepmodules/fcrn_igg_albumin_salvage_transcytosis.yaml

cargo receptor activityGO:0038024 endosomal lumen acidificationGO:0048388 endocytic recyclingGO:0032456 exocytosisGO:0006887 endosome to lysosome transportGO:0008333

GO:0038024

cargo receptor activity

pH-dependent endosomal binding of IgG and serum albumin by the FCGRT/B2M (FcRn) heterodimer at pH 5.5-6.0.

GO:0006898

receptor-mediated endocytosis

Clathrin-, AP-2-, and DNM2-dependent endocytic internalization at the endothelial/epithelial surface.

GO:0048388

endosomal lumen acidification

V-ATPase-driven proton translocation acidifies early endosomes to pH ~6.0, enabling histidine-dependent FcRn binding.

GO:0032456

endocytic recycling

EHD1- and SNAP23-dependent recycling and exocytic release of salvaged IgG and albumin at neutral plasma pH.

GO:0008333

endosome to lysosome transport

Unbound luminal protein cargo is routed via TSG101 and RAB7A to lysosomes for CTSD-mediated proteolysis.

PMID:36979511

Heme Scavenging and Delivery: The Role of Human Serum Albumin.

Human serum albumin binds the neonatal Fc receptor (FcRn) and crosses endothelial barriers via active receptor-mediated transcytotic and salvage mechanisms.

To date, eight membrane-associated HSA binding proteins have been described: albondin/glycoprotein 60 (gp60) [82], glycoprotein 18 (gp18) [83], glycoprotein 30 (gp30) [83], neonatal Fc Receptor (FcRn) [84]

PMID:28330995

Hepatic FcRn regulates albumin homeostasis and susceptibility to liver injury.

FcRn maintains the long circulatory half-life and high plasma levels of albumin and IgG by binding them in weakly acidic endosomes, diverting them from lysosomal degradation, and mediating recycling and bidirectional transcytosis.

The neonatal crystallizable fragment receptor (FcRn) is responsible for maintaining the long half-life and high levels of the two most abundant circulating proteins, albumin and IgG. In the latter case, the protective mechanism derives from FcRn binding to IgG in the weakly acidic environment contained within endosomes of hematopoietic and parenchymal cells, whereupon IgG is diverted from degradation in lysosomes and is recycled.

PMID:24469444

Structural insights into neonatal Fc receptor-based recycling mechanisms.

Crystal structure of human FcRn bound concurrently to human serum albumin (HSA) and IgG Fc demonstrates non-overlapping pH-dependent binding sites governed by histidine protonation (FcRn His161 for HSA and Fc His310 for IgG).

We report the three-dimensional structure of human neonatal Fc receptor (FcRn) bound concurrently to its two known ligands. More particularly, we solved the crystal structure of the complex between human FcRn, wild-type human serum albumin (HSA), and a human Fc engineered for improved pharmacokinetics properties (Fc-YTE).

file:human/ALB/ALB-ai-review.yaml

ALB gene review (human)

Extracellular serum carrier protein salvaged from lysosomal degradation by endosomal FcRn (UniProtKB:P02768, GO:0140104, GO:0005576).

file:human/FCGRT/FCGRT-ai-review.yaml

FCGRT gene review (human)

IgG receptor FcRn large subunit p51 mediating pH-dependent endosomal capture and recycling of IgG and albumin (UniProtKB:P55899, GO:0038024, GO:0032456).

file:human/B2M/B2M-ai-review.yaml

B2M gene review (human)

Essential beta-2-microglobulin light chain of the FcRn heterodimer required for FCGRT folding, stability, and endocytic recycling (UniProtKB:P61769, GO:0005198, GO:0032456).

file:human/AP2M1/AP2M1-ai-review.yaml

AP2M1 gene review (human)

AP-2 mu2 cargo adaptor recognizing cytoplasmic sorting motifs (UniProtKB:Q96CW1, GO:0005048, GO:0072583).

file:worm/dpy-23/dpy-23-ai-review.yaml

dpy-23 gene review (C. elegans)

Conserved metazoan AP-2 mu2 subunit recognizing cytoplasmic YxxPhi motifs for clathrin-dependent endocytosis (UniProtKB:P35603, GO:0035615, GO:0072583).

file:human/CLTC/CLTC-ai-review.yaml

CLTC gene review (human)

Clathrin heavy chain 1 lattice assembly for coated-pit internalization (UniProtKB:Q00610, GO:0005198, GO:0006898).

file:human/DNM2/DNM2-ai-review.yaml

DNM2 gene review (human)

Dynamin-2 GTPase driving endocytic vesicle scission (UniProtKB:P50570, GO:0061791, GO:0099050).

file:human/ATP6V1A/ATP6V1A-ai-review.yaml

ATP6V1A gene review (human)

V-ATPase catalytic subunit A driving early endosomal acidification to pH ~6.0 (UniProtKB:P38606, GO:0046961, GO:0048388).

file:human/EHD1/EHD1-ai-review.yaml

EHD1 gene review (human)

Recycling endosome tubulation and fission ATPase (UniProtKB:Q9H4M9, GO:0016887, GO:0032456).

file:human/SNAP23/SNAP23-ai-review.yaml

SNAP23 gene review (human)

Plasma-membrane Qbc-SNARE mediating recycling vesicle fusion and exocytic release at pH 7.4 (UniProtKB:O00161, GO:0005484, GO:0006887).

file:human/TSG101/TSG101-ai-review.yaml

TSG101 gene review (human)

ESCRT-I MVB cargo sorting subunit (UniProtKB:Q99816, GO:0043130, GO:0036258).

file:human/RAB7A/RAB7A-ai-review.yaml

RAB7A gene review (human)

Late endosomal maturation and lysosome transport GTPase (UniProtKB:P51149, GO:0003924, GO:0045022, GO:0008333).

file:human/CTSD/CTSD-ai-review.yaml

CTSD gene review (human)

Lysosomal aspartic protease executing catabolism of unsalvaged serum proteins (UniProtKB:P07339, GO:0004190, GO:0006508).

8Nodes

7Parts

0Variant Sets

0Variants

12Annotons

7Connections

Executable models all models

Agent-based derived from this module

Agent-based model of pH-dependent FcRn (FCGRT/B2M) IgG and albumin salvage, exocytic recycling, and lysosomal catabolism

✓ Wild-type FcRn salvage dominance (80% exocytic salvage/transcytosis vs. 20% lysosomal catabolism)
✓ FcRn / B2M deficiency or anti-FcRn blockade (efgartigimod; 100% diversion to lysosomal catabolism)
✓ V-ATPase acidification block (ATP6V1A loss / bafilomycin A1; failure of acidic histidine protonation switch)
✓ EHD1 / SNAP23 recycling & exocytosis block (FcRn-bound cargo trapped in recycling/sorting endosomes)
✓ RAB7A late-endosomal maturation block (eliminates lysosomal catabolism and routes 100% of cargo to FcRn salvage)
✓ Clathrin / DNM2 endocytic uptake block (albumin and IgG retained in extracellular plasma pool)

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Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:fcrn_igg_albumin_salvage_transcytosis deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

13 gene-function check(s) reflected in core functions · 0 conflict(s) · 10 evidence or coverage gap(s) (26 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

Annoton	Participant	Function	Assessment
alb_extracellular_carrier	ALB (human) UniProtKB:P02768 Family Representative	molecular carrier activity GO:0140104	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap2m1_cargo_selection	AP2M1 (human) UniProtKB:Q96CW1 Family Representative	signal sequence receptor activity GO:0005048	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ap2m1_cargo_selection	dpy-23 (C. elegans) UniProtKB:P35603 Family Representative	signal sequence receptor activity GO:0005048	Function Unreviewed No retained annotation or core molecular function supports this GO assertion. Missing or broader evidence is a coverage gap, not proof the activity is absent.
cltc_coat_lattice	CLTC (human) UniProtKB:Q00610 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dnm2_vesicle_scission	DNM2 (human) UniProtKB:P50570 Family Representative	GTPase motor activity GO:0061791	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
atp6v1a_proton_pump	ATP6V1A (human) UniProtKB:P38606 Family Representative	proton-transporting ATPase activity, rotational mechanism GO:0046961	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fcgrt_salvage_receptor	FCGRT (human) UniProtKB:P55899 Family Representative	cargo receptor activity GO:0038024	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
b2m_fcrn_light_chain	B2M (human) UniProtKB:P61769 Family Representative	structural molecule activity GO:0005198	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ehd1_membrane_fission	EHD1 (human) UniProtKB:Q9H4M9 Family Representative	ATP hydrolysis activity GO:0016887	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
snap23_exocytic_fusion	SNAP23 (human) UniProtKB:O00161 Family Representative	SNAP receptor activity GO:0005484	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
tsg101_escrt_sorting	TSG101 (human) UniProtKB:Q99816 Family Representative	ubiquitin binding GO:0043130	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rab7a_late_maturation	RAB7A (human) UniProtKB:P51149 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
rab7a_late_maturation	Rab7 (mouse) UniProtKB:P51150 Family Representative	GTPase activity GO:0003924	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
ctsd_proteolysis	CTSD (human) UniProtKB:P07339 Family Representative	aspartic-type endopeptidase activity GO:0004190	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
alb_extracellular_carrier	Serum albumin PANTHER:PTHR11385:SF15 Family	molecular carrier activity GO:0140104	Family Review Missing No supported structured family review is available for PANTHER:PTHR11385:SF15.
ap2m1_cargo_selection	AP-2 complex subunit mu PANTHER:PTHR10529:SF236 Family	signal sequence receptor activity GO:0005048	Family Supported Family review supports GO:0005048 FAMILY_WIDE. Mu subunits across AP-1, AP-2, AP-3, and AP-4 directly bind peptide sorting signals (such as YxxPhi motifs) in the cytosolic tails of transmembrane cargos via a conserved hydrophobic pocket on the C-terminal MHD beta-sandwich.
cltc_coat_lattice	Clathrin heavy chain 1 PANTHER:PTHR10292:SF7 Family	structural molecule activity GO:0005198	Family Review Missing No supported structured family review is available for PANTHER:PTHR10292:SF7.
dnm2_vesicle_scission	Dynamin-2 PANTHER:PTHR11566:SF23 Family	GTPase motor activity GO:0061791	Family Review Missing No supported structured family review is available for PANTHER:PTHR11566:SF23.
atp6v1a_proton_pump	V-type proton ATPase catalytic subunit A PANTHER:PTHR43607:SF9 Family	proton-transporting ATPase activity, rotational mechanism GO:0046961	Family Review Missing No supported structured family review is available for PANTHER:PTHR43607:SF9.
fcgrt_salvage_receptor	IgG receptor FcRn large subunit p51 PANTHER:PTHR16675:SF3 Family	cargo receptor activity GO:0038024	Family Supported Family review supports GO:0038024 for PANTHER:PTHR16675:SF3. Specific to the neonatal Fc receptor heavy chain (PANTHER:PTHR16675:SF3, FCGRT), which functions as an endosomal pH-dependent salvage and transcytosis cargo receptor for monomeric IgG and serum albumin.
b2m_fcrn_light_chain	Beta-2-microglobulin PANTHER:PTHR19944:SF62 Family	structural molecule activity GO:0005198	Family Supported Family review supports GO:0005198 for PANTHER:PTHR19944:SF62. Beta-2-microglobulin (PANTHER:PTHR19944:SF62, B2M) acts as an obligate non-polymorphic structural beta-chain subunit that stabilizes the fold of MHC class I heavy chains, CD1, MR1, HFE, and the neonatal Fc receptor heavy chain FCGRT (GO:0005198).
ehd1_membrane_fission	EH domain-containing protein 1 PANTHER:PTHR11216:SF127 Family	ATP hydrolysis activity GO:0016887	Family Review Missing No supported structured family review is available for PANTHER:PTHR11216:SF127.
snap23_exocytic_fusion	Synaptosomal-associated protein 23 PANTHER:PTHR19305:SF4 Family	SNAP receptor activity GO:0005484	Family Review Missing No supported structured family review is available for PANTHER:PTHR19305:SF4.
tsg101_escrt_sorting	Tumor susceptibility gene 101 protein PANTHER:PTHR23306:SF17 Family	ubiquitin binding GO:0043130	Family Review Missing No supported structured family review is available for PANTHER:PTHR23306:SF17.
rab7a_late_maturation	Ras-related protein Rab-7a PANTHER:PTHR47981:SF13 Family	GTPase activity GO:0003924	Family Review Missing No supported structured family review is available for PANTHER:PTHR47981:SF13.
ctsd_proteolysis	Cathepsin D PANTHER:PTHR47966:SF42 Family	aspartic-type endopeptidase activity GO:0004190	Family Review Missing No supported structured family review is available for PANTHER:PTHR47966:SF42.

Feedback loops (advisory, prose-driven: a regulator counts as "feedback" when its own description says so)

✓ every negative regulator described as feedback has an upstream edge closing the loop.

fcrn_ph_dependent_salvage ⊣ rab7_late_endosome_routing [closed]
fcrn_ph_dependent_salvage is regulated by early_endosome_acidification: feedback loop closed

Gene-review completeness (14/14 grounded genes reviewed)

7 complete review(s) · 6 with deep research · 0 missing review · 8 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ALB P02768	✓	58/66	✗
AP2M1 Q96CW1	✓	129/184	✗
ATP6V1A P38606	✓	✓	✓
B2M P61769	✓	175/176	✗
CLTC Q00610	✓	✓	✓
CTSD P07339	✓	84/91	✗
DNM2 P50570	✓	170/171	✗
dpy-23 P35603	✓	22/23	✓
EHD1 Q9H4M9	✓	✓	✓
FCGRT P55899	✓	✓	✗
Rab7 P51150	✓	✓	✓
RAB7A P51149	✓	✓	✓
SNAP23 O00161	✓	72/73	✗
TSG101 Q99816	✓	✓	✗

Tree

Neonatal Fc receptor (FCGRT/B2M) pH-dependent IgG and albumin salvage, exocytic recycling, and lysosomal catabolismTransport Stepfcrn_igg_albumin_salvage_transcytosis

Parts
1. 1. extracellular plasma pool of serum albumin (ALB) and IgG / Fc-fusion biologics at neutral pH (7.4)
2. Extracellular serum albumin (ALB) & IgG / Fc-biologic plasma pool (pH 7.4)Molecular Functionalb_igg_extracellular_pool
  
  Annotons
  - ALB (HSA): circulating serum albumin and FcRn salvage substrate Family: Serum albumin
3. 2. clathrin/AP-2 coated-pit capture, pinocytic uptake, and DNM2 vesicle scission
4. Clathrin/AP-2 endocytic uptake and DNM2 vesicle scissionTransport Stepclathrin_dnm2_endocytic_uptake
  
  Annotons
  - AP2M1 (AP-2 mu2): clathrin-coated pit cargo adaptor Family: AP-2 complex subunit mu
  - CLTC (CHC17): clathrin heavy chain coat lattice Family: Clathrin heavy chain 1
  - DNM2 (dynamin-2): coated-vesicle neck scission GTPase Family: Dynamin-2
5. 3. V-ATPase early endosome acidification (pH ~6.0) and histidine protonation of IgG and albumin
6. V-ATPase early endosome acidification (pH ~6.0 histidine protonation switch)Transport Stepearly_endosome_acidification
  
  Annotons
  - ATP6V1A: V-ATPase catalytic subunit A Family: V-type proton ATPase catalytic subunit A
7. 4. FCGRT/B2M (FcRn) acidic pH-dependent capture and salvage sorting of protonated IgG and albumin
8. FCGRT/B2M (FcRn) acidic endosome capture (pH 6.0 salvage receptor complex)Molecular Functionfcrn_ph_dependent_salvage
  
  Annotons
  - FCGRT (FcRn alpha chain p51): pH-dependent IgG and albumin salvage receptor Family: IgG receptor FcRn large subunit p51
  - B2M (beta-2-microglobulin): obligatory FcRn heterodimer light chain Family: Beta-2-microglobulin
9. 5. EHD1 tubular recycling and SNAP23-mediated exocytic fusion and cargo release at neutral pH (7.4)
10. EHD1 recycling tubulation & SNAP23 exocytic release / transcytosis (pH 7.4 uncoupling)Transport Stepehd1_snap23_salvage_exocytosis
  
  Annotons
  - EHD1: recycling endosome tubulation/fission ATPase Family: EH domain-containing protein 1
  - SNAP23: plasma-membrane Qbc-SNARE for recycling vesicle exocytosis Family: Synaptosomal-associated protein 23
11. 6. ESCRT-I MVB sorting and RAB7A-mediated late endosome routing of unbound luminal cargo
12. TSG101/ESCRT-I and RAB7A late endosome routing of unsalvaged cargoTransport Steprab7_late_endosome_routing
  
  Annotons
  - TSG101: ESCRT-I ubiquitin-binding MVB sorting subunit Family: Tumor susceptibility gene 101 protein
  - RAB7A / Rab7: late endosome maturation and lysosome-tethering GTPase Family: Ras-related protein Rab-7a
13. 7. lysosomal fusion and CTSD-mediated proteolytic catabolism of unsalvaged IgG and albumin
14. Lysosomal fusion and CTSD proteolytic catabolism of unsalvaged IgG & albuminMolecular Functionctsd_lysosomal_catabolism
  
  Annotons
  - CTSD (cathepsin D): lysosomal aspartic endopeptidase Family: Cathepsin D

Details

Neonatal Fc receptor (FCGRT/B2M) pH-dependent IgG and albumin salvage, exocytic recycling, and lysosomal catabolismTransport Stepfcrn_igg_albumin_salvage_transcytosis

cargo receptor activityGO:0038024 endosomal lumen acidificationGO:0048388 endocytic recyclingGO:0032456 exocytosisGO:0006887 endosome to lysosome transportGO:0008333

Constructed for the DELIVEROME and ABM_TRAFFICKING projects to represent pH-dependent FcRn (FCGRT/B2M) salvage and transcytosis of IgG, Fc-fusion biologics, and serum albumin as an executable agent-based model (ABM) derived directly from the module graph. All protein participants are grounded to completed AIGR gene reviews (human ALB, FCGRT, B2M, AP2M1, CLTC, DNM2, ATP6V1A, EHD1, SNAP23, TSG101, RAB7A, CTSD, and mouse Rab7) and verified PANTHER family/subfamily identifiers.

Connections

alb_igg_extracellular_pool -> clathrin_dnm2_endocytic_uptake Provides Input For

Extracellular albumin and IgG are internalized from plasma via fluid-phase pinocytosis and clathrin/AP-2/DNM2-coated pits.

clathrin_dnm2_endocytic_uptake -> early_endosome_acidification Provides Input For

Internalized endocytic vesicles deliver luminal IgG and albumin to V-ATPase-acidified early sorting endosomes (pH ~6.0).

early_endosome_acidification -> fcrn_ph_dependent_salvage Provides Input For

Protonated IgG and albumin in acidified sorting endosomes bind endosomal FCGRT/B2M (FcRn) heterodimers with high affinity.

early_endosome_acidification -> rab7_late_endosome_routing Provides Input For

Unbound luminal cargo remaining in the sorting endosome progresses into TSG101/RAB7A late endosomes.

fcrn_ph_dependent_salvage -> rab7_late_endosome_routing Negatively Regulates

High-affinity pH-dependent capture of IgG and albumin by endosomal FCGRT/B2M sequesters cargo into recycling tubules and protects it from RAB7A-mediated late-endosomal/lysosomal degradation (PMID:28330995, PMID:36979511).

fcrn_ph_dependent_salvage -> ehd1_snap23_salvage_exocytosis Provides Input For

FcRn-bound IgG and albumin enter EHD1 recycling tubules and undergo SNAP23-mediated exocytic fusion and release at pH 7.4.

rab7_late_endosome_routing -> ctsd_lysosomal_catabolism Provides Input For

Mature RAB7A-positive late endosomes fuse with lysosomes where CTSD catabolizes unsalvaged IgG and albumin.

Part 1: extracellular plasma pool of serum albumin (ALB) and IgG / Fc-fusion biologics at neutral pH (7.4)

Extracellular serum albumin (ALB) & IgG / Fc-biologic plasma pool (pH 7.4)Molecular Functionalb_igg_extracellular_pool

Annotons

ALB (HSA): circulating serum albumin and FcRn salvage substrate

alb_extracellular_carrier

Participant: Family: Serum albumin

Family:

Serum albuminPANTHER:PTHR11385:SF15

Representative Members: ALB (human)UniProtKB:P02768

Function

molecular carrier activityGO:0140104

Substrates: endogenous metabolites, heme/bilirubin, fatty acids, and albumin-bound therapeutics

Processes

bilirubin transportGO:0015723 transportGO:0006810

Locations

extracellular regionGO:0005576

Circulates in plasma at neutral pH (7.4) where it does not bind cell-surface FcRn, entering vascular endothelial and myeloid cells continuously via pinocytosis and clathrin-coated pits.

Part 2: clathrin/AP-2 coated-pit capture, pinocytic uptake, and DNM2 vesicle scission

Clathrin/AP-2 endocytic uptake and DNM2 vesicle scissionTransport Stepclathrin_dnm2_endocytic_uptake

Annotons

AP2M1 (AP-2 mu2): clathrin-coated pit cargo adaptor

ap2m1_cargo_selection

Participant: Family: AP-2 complex subunit mu

Family:

AP-2 complex subunit muPANTHER:PTHR10529:SF236

Representative Members: AP2M1 (human)UniProtKB:Q96CW1 dpy-23 (C. elegans)UniProtKB:P35603

Function

signal sequence receptor activityGO:0005048

Processes

clathrin-dependent endocytosisGO:0072583 receptor internalizationGO:0031623

Locations

clathrin-coated pitGO:0005905

Couples plasma-membrane FcRn (via tryptophan- and dileucine-based motifs in the FCGRT cytoplasmic tail) and co-internalized fluid-phase cargo into clathrin-coated pits.

CLTC (CHC17): clathrin heavy chain coat lattice

cltc_coat_lattice

Participant: Family: Clathrin heavy chain 1

Family:

Clathrin heavy chain 1PANTHER:PTHR10292:SF7

Representative Members: CLTC (human)UniProtKB:Q00610

Function

structural molecule activityGO:0005198

Processes

receptor-mediated endocytosisGO:0006898 clathrin coat assemblyGO:0048268

Locations

clathrin-coated endocytic vesicleGO:0045334

Forms the polyhedral coat driving budding of endocytic vesicles containing luminal IgG and albumin.

DNM2 (dynamin-2): coated-vesicle neck scission GTPase

dnm2_vesicle_scission

Participant: Family: Dynamin-2

Family:

Dynamin-2PANTHER:PTHR11566:SF23

Representative Members: DNM2 (human)UniProtKB:P50570

Function

GTPase motor activityGO:0061791

Processes

vesicle scissionGO:0099050 receptor-mediated endocytosisGO:0006898

Locations

clathrin-coated pitGO:0005905

Catalyzes GTP-dependent neck fission to release nascent endocytic vesicles into the endothelial/epithelial cytoplasm.

Part 3: V-ATPase early endosome acidification (pH ~6.0) and histidine protonation of IgG and albumin

V-ATPase early endosome acidification (pH ~6.0 histidine protonation switch)Transport Stepearly_endosome_acidification

Annotons

ATP6V1A: V-ATPase catalytic subunit A

atp6v1a_proton_pump

Participant: Family: V-type proton ATPase catalytic subunit A

Family:

V-type proton ATPase catalytic subunit APANTHER:PTHR43607:SF9

Representative Members: ATP6V1A (human)UniProtKB:P38606

Function

proton-transporting ATPase activity, rotational mechanismGO:0046961

Processes

endosomal lumen acidificationGO:0048388 proton transmembrane transportGO:1902600

Locations

endosome membraneGO:0010008 lysosomal membraneGO:0005765

Lowers the early sorting endosome pH to ~5.5-6.0, protonating key histidine residues on internalized IgG (CH2-CH3 hinge) and albumin (domain III) to enable high-affinity capture by endosomal FcRn.

Part 4: FCGRT/B2M (FcRn) acidic pH-dependent capture and salvage sorting of protonated IgG and albumin

FCGRT/B2M (FcRn) acidic endosome capture (pH 6.0 salvage receptor complex)Molecular Functionfcrn_ph_dependent_salvage

Context

early endosome membraneGO:0031901

Annotons

FCGRT (FcRn alpha chain p51): pH-dependent IgG and albumin salvage receptor

fcgrt_salvage_receptor

Participant: Family: IgG receptor FcRn large subunit p51

Family:

IgG receptor FcRn large subunit p51PANTHER:PTHR16675:SF3

Representative Members: FCGRT (human)UniProtKB:P55899

Function

cargo receptor activityGO:0038024

Substrates: protonated IgG (CH2-CH3 domain) and serum albumin (ALB domain III) at pH 5.5-6.0

Processes

endocytic recyclingGO:0032456 receptor-mediated endocytosisGO:0006898

Locations

early endosome membraneGO:0031901 recycling endosome membraneGO:0055038

Captures protonated IgG and albumin in the acidic sorting endosome lumen and partitions the receptor-cargo complex into recycling/transcytotic tubules, actively preventing luminal progression to late endosomes.

B2M (beta-2-microglobulin): obligatory FcRn heterodimer light chain

b2m_fcrn_light_chain

Participant: Family: Beta-2-microglobulin

Family:

Beta-2-microglobulinPANTHER:PTHR19944:SF62

Representative Members: B2M (human)UniProtKB:P61769

Function

structural molecule activityGO:0005198

Processes

endocytic recyclingGO:0032456

Locations

early endosome membraneGO:0031901

Forms the obligatory invariant light chain of the FcRn heterodimer; loss of B2M abolishes FCGRT surface/endosomal expression and causes severe IgG and albumin hypercatabolism.

Part 5: EHD1 tubular recycling and SNAP23-mediated exocytic fusion and cargo release at neutral pH (7.4)

EHD1 recycling tubulation & SNAP23 exocytic release / transcytosis (pH 7.4 uncoupling)Transport Stepehd1_snap23_salvage_exocytosis

Annotons

EHD1: recycling endosome tubulation/fission ATPase

ehd1_membrane_fission

Participant: Family: EH domain-containing protein 1

Family:

EH domain-containing protein 1PANTHER:PTHR11216:SF127

Representative Members: EHD1 (human)UniProtKB:Q9H4M9

Function

ATP hydrolysis activityGO:0016887

Processes

endocytic recyclingGO:0032456

Locations

recycling endosome membraneGO:0055038

Generates tubular recycling carriers that transport FcRn-IgG and FcRn-albumin complexes from sorting endosomes toward the plasma membrane.

SNAP23: plasma-membrane Qbc-SNARE for recycling vesicle exocytosis

snap23_exocytic_fusion

Participant: Family: Synaptosomal-associated protein 23

Family:

Synaptosomal-associated protein 23PANTHER:PTHR19305:SF4

Representative Members: SNAP23 (human)UniProtKB:O00161

Function

SNAP receptor activityGO:0005484

Processes

exocytosisGO:0006887 vesicle fusionGO:0006906 endocytic recyclingGO:0032456

Locations

plasma membraneGO:0005886

Mediates fusion of FcRn-bearing recycling tubules with the plasma membrane, exposing bound IgG and albumin to neutral extracellular pH (7.4) for immediate release into the circulation or transcytotic space.

Part 6: ESCRT-I MVB sorting and RAB7A-mediated late endosome routing of unbound luminal cargo

TSG101/ESCRT-I and RAB7A late endosome routing of unsalvaged cargoTransport Steprab7_late_endosome_routing

Context

late endosome membraneGO:0031902

Annotons

TSG101: ESCRT-I ubiquitin-binding MVB sorting subunit

tsg101_escrt_sorting

Participant: Family: Tumor susceptibility gene 101 protein

Family:

Tumor susceptibility gene 101 proteinPANTHER:PTHR23306:SF17

Representative Members: TSG101 (human)UniProtKB:Q99816

Function

ubiquitin bindingGO:0043130

Processes

multivesicular body assemblyGO:0036258 ubiquitin-dependent protein catabolic process via the multivesicular body sorting pathwayGO:0043162

Locations

late endosome membraneGO:0031902 early endosome membraneGO:0031901

Routes non-salvaged luminal cargo and ubiquitinated membrane proteins into maturing multivesicular bodies.

RAB7A / Rab7: late endosome maturation and lysosome-tethering GTPase

rab7a_late_maturation

Participant: Family: Ras-related protein Rab-7a

Family:

Ras-related protein Rab-7aPANTHER:PTHR47981:SF13

Representative Members: RAB7A (human)UniProtKB:P51149 Rab7 (mouse)UniProtKB:P51150

Function

GTPase activityGO:0003924

Processes

early endosome to late endosome transportGO:0045022 endosome to lysosome transportGO:0008333

Locations

late endosomeGO:0005770 late endosome membraneGO:0031902

Commits unbound luminal IgG and albumin that failed FcRn capture to late endosomes and lysosomal fusion.

Part 7: lysosomal fusion and CTSD-mediated proteolytic catabolism of unsalvaged IgG and albumin

Lysosomal fusion and CTSD proteolytic catabolism of unsalvaged IgG & albuminMolecular Functionctsd_lysosomal_catabolism

Annotons

CTSD (cathepsin D): lysosomal aspartic endopeptidase

ctsd_proteolysis

Participant: Family: Cathepsin D

Family:

Cathepsin DPANTHER:PTHR47966:SF42

Representative Members: CTSD (human)UniProtKB:P07339

Function

aspartic-type endopeptidase activityGO:0004190

Processes

proteolysisGO:0006508

Locations

lysosomal lumenGO:0043202 endosome lumenGO:0031904

Hydrolyzes unsalvaged IgG and albumin delivered to the lysosomal lumen, accounting for fractional catabolic clearance (and accelerated clearance under FcRn blockade).