MFGE8 (lactadherin) – curation notes

Provenance note: Provider deep research failed (Falcon returned HTTP 402 Payment
Required; Perplexity not configured). No -deep-research-<provider>.md file exists. The
synthesis below replaces it and was assembled manually from the UniProt record (Q08431),
cached publications in publications/, and PubMed searches (E-utilities) used only to locate
PMIDs, which were then cached with just fetch-gene-pmids human MFGE8.

Identity and architecture

• UniProt Q08431, lactadherin / MFG-E8 / BA46 / SED1; secreted glycoprotein, 387 aa precursor
  (signal peptide 1-23). Human protein has one N-terminal EGF-like domain (24-67) carrying the
  RGD integrin-binding motif (46-48), followed by two discoidin (F5/8 type C) domains, C1
  (70-225) and C2 (230-387). (UniProt FT lines.)
• UniProt: "The F5/8 type C 2 domain mediates high-affinity binding to phosphatidylserine-containing
  membranes" (ECO:0000250).
• Chains: lactadherin (24-387), lactadherin short form (202-387), and medin (268-317).
• Mouse Mfge8 has two EGF domains; the RGD sits in EGF2 PMID:19204935. Human has a single EGF domain with the RGD.

Core activity: phosphatidylserine-bridging opsonin

• Discovery (mouse): PMID:12000961 An RGE mutant acts as dominant negative and blocks
  macrophage engulfment in vitro and in vivo.
• In vivo requirement (mouse): PMID:15155946
• Domain logic: C-terminal discoidin domains bind PS; RGD binds αv integrins on the phagocyte
  PMID:19204935.
• Human protein: PMID:19204935; human SLE-associated truncation mutant still
  PMID:20213738.
• Structural basis (bovine C2 domain, 1.7 Å) PMID:18160406. Lactadherin also competes with factors V/VIII for PS sites and is anticoagulant in
  vitro (same abstract).
• Lactadherin is used as a PS probe, detecting low-density PS exposure earlier than annexin V
  PMID:17123296.
• Human genetics: rare intronic MFGE8 variant creating a cryptic exon in 2/322 female SLE patients
  PMID:20213738.

Neuronal / synaptic opsonization (phagoptosis)

• PMID:22357850; in LPS neuroinflammation, MFG-E8 drives microglial phagocytosis of viable
  neurons; neuronal loss absent in Mfge8 KO cultures and restored by recombinant MFG-E8 (mouse/rat).
• Aβ-induced neuronal loss in mixed cultures is MFG-E8 dependent PMID:23647050.
• Human AD (ex vivo / cultured human glia): synaptoneurosomes from AD brain carry more MFG-E8;
  blocking the integrin-binding site of MFG-E8 reduces astrocytic and microglial ingestion of AD
  (but not control) synapses; blocking astrocytic integrin αvβ5 has a similar effect
  [PMID:37652017 "AD promotes increased synapse ingestion by human glial cells at least in part via
  an MFG-E8 opsonophagocytic mechanism"; "One possible mechanism for tagging synapses for ingestion
  is via MFG-E8, a phosphatidylserine-recognizing opsonin."]. Note: PS on the synapses was not
  directly measured in this paper; the PS link is inferred ("MFG-E8 protein is likely increased on
  AD synapses due to binding phosphatidylserine").
• Curation caveat (for cross-checking downstream disease models): MFG-E8 is not a complement
  component; its synapse-tagging mechanism is PS-bridging to integrins (αvβ3/αvβ5), parallel to
  but distinct from C1q/C3-mediated pruning. Grouping it under a "complement-mediated" node is a
  mechanistic simplification.

Other roles (mostly mouse, non-core for GO MF)

• Intestinal epithelial repair: PMID:18008006
• VEGF-dependent neovascularization via αvβ3/αvβ5 PMID:15834428.
• Collagen uptake / anti-fibrotic (mouse) PMID:19884654.
• Sperm–zona pellucida adhesion (pig/mouse SED1) PMID:19204935; sperm-associated
  protein is largely epididymal and sits on the anterior dorsal plasma membrane over the acrosome.

Medin (vascular amyloid)

• PMID:10411933 Aortic medial amyloid occurs in virtually all individuals over 60; lactadherin
  is made by aortic medial smooth muscle cells.
• Medin aggregation causes cerebrovascular dysfunction in aged wild-type mice PMID:32900929.
• PMID:36385530 Medin
  co-localizes with vascular Aβ (CAA); medin deficiency halves vascular Aβ in mice; MFGE8
  expression rises in AD (ROSMAP).
• Medin formation is pathological/age-related, not a physiological GO function of the gene
  product; captured in description only.

Annotation review summary decisions

• PS binding (IBA, IPI) and integrin binding (IEA) – ACCEPT; core bridging activities.
• Apoptotic cell clearance (IEA from mouse) – ACCEPT; core BP.
• ECM structural constituent (RCA, matrisome-based ×4) – MARK_AS_OVER_ANNOTATED: MFG-E8 is a
  soluble bridging opsonin; no structural role.
• Extracellular region / external side of PM / membrane – ACCEPT or non-core.
• Exosome / EV / ECM HDA, interstitial matrix TAS, acrosomal membrane IEA, ER lumen TAS
  (FAM20C reaction, transit) – KEEP_AS_NON_CORE.
• No NEW annotations proposed. "Synapse pruning" was considered but evidence is limited to an
  antibody-blocking assay in a disease context; raised as a question instead.