# LMAN2 (VIP36) — Gene Review Notes UniProt: Q12907 (LMAN2_HUMAN). Gene symbol: LMAN2 (HGNC:16986), synonym C5orf8. Protein name: Vesicular integral-membrane protein VIP36 (also Glycoprotein GP36b, Lectin mannose-binding 2). 356 aa precursor; signal peptide 1-44; mature chain 45-356; single-pass type I membrane protein (lumenal 45-322, TM 323-345, cytoplasmic 346-356). ## What VIP36 is VIP36/LMAN2 is a type I transmembrane **leguminous-type (L-type) lectin** of the early secretory pathway. Its lumenal L-type lectin-like domain (52-276) binds carbohydrate in a Ca2+-dependent manner [file:human/LMAN2/LMAN2-uniprot.txt "L-type lectin-like"; UniProt COFACTOR "Binds 2 calcium ions per subunit"]. UniProt FUNCTION: "Plays a role as an intracellular lectin in the early secretory pathway. Interacts with N-acetyl-D-galactosamine and high-mannose type glycans and may also bind to O-linked glycans. Involved in the transport and sorting of glycoproteins carrying high mannose-type glycans" [file:human/LMAN2/LMAN2-uniprot.txt]. It is a member of the same L-type lectin family as LMAN1/ERGIC-53 (P49257; PANTHER PTN000259611). It is NOT a glycosidase / mannosidase — it has no catalytic activity; it is a carbohydrate-binding cargo/sorting receptor. The CDD/InterPro signatures are lectin signatures (cd06901 lectin_VIP36_VIPL; IPR035664 VIP36_lectin; PF03388 Lectin_leg-like). ## Localization (core CC = ERGIC/Golgi/ER membrane of the early secretory pathway) UniProt SUBCELLULAR LOCATION (from PubMed:10444376, Fullekrug et al. "VIP36 localisation to the early secretory pathway"): "Endoplasmic reticulum-Golgi intermediate compartment membrane ... Golgi apparatus membrane ... Endoplasmic reticulum membrane" [file:human/LMAN2/LMAN2-uniprot.txt]. It cycles early in the secretory pathway between ER/ERGIC and Golgi. - ERGIC IDA: [PMID:20477988 "The VIP36/alpha1-AT complex localized to Golgi and endoplasmic reticulum (ER)"] and the localization of VIP36 to Golgi/ER cycling. - ERGIC IDA: [PMID:15308636] ERGIC membrane proteomics from BFA-treated HepG2 cells — "purification of ERGIC membranes ... enriched 110-fold over the homogenate for ERGIC-53"; VIP36 was among the cycling/cargo-receptor proteins in this ERGIC-enriched fraction. - Golgi apparatus IDA: HPA immunofluorescence (GO_REF:0000052) and [PMID:20477988 "VIP36 localizes to the Golgi apparatus and cycles early in the secretory pathway"]. ## Carbohydrate / D-mannose binding (core MF) - In vitro VIP36 binds high-mannose glycans with a pH optimum ~6.5: [PMID:20477988 "In vitro, VIP36 binds high-mannose glycans with a pH optimum of 6.5, a value similar to the luminal pH of the Golgi apparatus"]. - In the living cell VIP36 bound exclusively the high-mannose form of its cargo: [PMID:20477988 "In the living cell, VIP36 bound exclusively to the high-mannose form of alpha1-AT. The binding was increased when complex glycosylation was prevented by kifunensine and abolished when the glycosylation sites of alpha1-AT were inactivated by mutagenesis"]. This is the basis for the D-mannose binding IMP. - Quantitative lectin-glycan binding (carbohydrate binding IDA): [PMID:23701871 "Estimated Ka values of malectin and VIP36 were in good agreement indeed with those evaluated by conventional methods such as isothermal titration calorimetry (ITC) or frontal affinity chromatography (FAC)"] using "fluorescently labeled high-mannose-type glycans and recombinant intracellular lectins." ## Transport / sorting / quality control (core BP) VIP36 functions in post-ER quality control and ER<->Golgi cycling of high-mannose glycoproteins: - Silencing VIP36 accelerated cargo transport, arguing against a pure anterograde role and consistent with a quality-control / retrograde recycling role: [PMID:20477988 "Silencing VIP36 accelerated alpha1-AT transport, arguing against a role of VIP36 in anterograde traffic"]. - Retrograde Golgi-to-ER recycling (basis for GO:0006890 IMP): [PMID:20477988 "The complex formed by VIP36 and alpha1-AT in the Golgi recycled back to the ER. The combined data are most consistent with a function of VIP36 in post-ER quality control of alpha1-AT"]. - VIP36 is "postulated as a cargo receptor for Golgi-to-endoplasmic reticulum transport" [PMID:22016386]. - Reactome: COPII-mediated vesicle transport (R-HSA-204005); Cargo concentration in the ER (R-HSA-5694530); consistent with COPII vesicle (GO:0030134) and ER-to-Golgi transport (GO:0006888) IBA annotations. ## Interactions - alpha1-antitrypsin (SERPINA1, P01009) is a glycoprotein cargo identified by YFP-fragment complementation: source of the protein binding IPI (WITH P01009). [PMID:20477988 "we identified the glycoprotein alpha1-antitrypsin (alpha1-AT) as a cargo of VIP36"]. This is a lectin-cargo (sugar-dependent) interaction; the bare "protein binding" GO term is uninformative and the real informative MF is the mannose/carbohydrate binding. - heat shock protein binding IPI (GO:0031072), WITH UniProtKB:P11021 (BiP / HSPA5 / GRP78): recorded by UniProt from PMID:20477988. P11021 is the ER chaperone BiP. This is a specific, more-informative interaction than bare protein binding but is not the defining sorting mechanism; kept non-core. (The cached PMID:20477988 entry is abstract-only — full_text_available: false — so the BiP interaction detail is in the full text seen by the curator, not the abstract.) ## Secondary / cell-surface role (ectodomain shedding, macrophages) A minor pool of Endo-H-resistant (late-Golgi / cell-surface) VIP36 reaches the plasma membrane and is shed; the shed/cell-surface VIP36 regulates phagocytosis in macrophages: - [PMID:22016386 "the shedding of VIP36 occurs mainly on the cell surface"] - [PMID:22016386 "VIP36 significantly accumulates on the cell surface upon inhibition of shedding"] - [PMID:22016386 "the amount of VIP36 precisely regulates phagocytosis in macrophages and that the shedding of VIP36 is required for this regulation"] This is the basis for the extracellular region / plasma membrane / cell surface IDA and the positive regulation of phagocytosis IMP/IEA. These are genuine but secondary to the core ER-Golgi lectin/sorting function, which dominates the protein's biology. Notably the lectin activity is dispensable for phagocytosis enhancement [PMID:22016386 "the lectin activity is dispensable for the enhancement of phagocytosis"], underscoring that this is a separate moonlighting role rather than the core function. ## Proteomics-only localizations (non-core / over-annotation) - extracellular exosome (GO:0070062) HDA from urinary/prostatic exosome shotgun proteomics [PMID:23533145; PMID:19056867] — large-scale proteomic catalogs (~900-1132 proteins), no VIP36-specific functional claim; reflects presence in secreted vesicles, not core residence. - membrane (GO:0016020) IEA (InterPro IPR005052) — bare "membrane" is uninformative; the protein is specifically an ER/ERGIC/Golgi single-pass membrane protein. ## Cofactor / metal Lectin domain binds 2 Ca2+ per subunit as a structural cofactor required for carbohydrate binding [file:human/LMAN2/LMAN2-uniprot.txt COFACTOR "Binds 2 calcium ions per subunit"]; multiple Ca2+-binding residues (162, 164, 166, 193). UniProt keyword "Metal-binding" / GO:0046872 metal ion binding (IEA) is a structural attribute, not the core function. (No metal/calcium binding row is present in the GOA TSV stub, so no annotation is reviewed for it.) ## Summary of review decisions - Core MF: D-mannose binding (GO:0005537), carbohydrate binding (GO:0030246) — ACCEPT. - Core CC: ERGIC (GO:0005793), ERGIC membrane (GO:0033116), Golgi membrane (GO:0000139), Golgi apparatus (GO:0005794), ER membrane (GO:0005789), COPII vesicle (GO:0030134) — ACCEPT. - Core BP: ER-to-Golgi vesicle-mediated transport (GO:0006888), retrograde Golgi-to-ER transport (GO:0006890) — ACCEPT. - heat shock protein binding (GO:0031072), protein binding (GO:0005515) — KEEP_AS_NON_CORE. - positive regulation of phagocytosis (GO:0050766, IMP + IEA) — KEEP_AS_NON_CORE (secondary macrophage role); IEA ortholog one MARK_AS_OVER_ANNOTATED. - extracellular region/plasma membrane/cell surface (22016386 IDA) — KEEP_AS_NON_CORE (shedding). - extracellular exosome (HDA), membrane (IEA) — MARK_AS_OVER_ANNOTATED. ## Falcon deep-research findings (incorporated 2026-06) - Specific ectodomain-shedding cleavage site (mechanism for the existing cell-surface/shedding role): quantitative protein terminomics maps VIP36/LMAN2 as a metalloprotease-regulated shedding substrate cleaved at **F298 down-arrow L299 (SVNF/LKSP)**, reproducible across multiple cell lines and suppressed by the broad-spectrum metalloprotease inhibitor BB-94 [PMID:33796845 (Tsumagari et al., iScience 2021) "Exploring the landscape of ectodomain shedding by quantitative protein terminomics"; DOI 10.1016/j.isci.2021.102476]. This refines the mechanistic basis of the previously curated cell-surface/plasma-membrane/extracellular-region IDA and the shedding-dependent phagocytosis role (PMID:22016386). Added as MEDIUM-relevance reference; no annotation change (shedding already KEEP_AS_NON_CORE). - Glycan-binding specificity detail (Falcon synthesis of prior reviews; consistent with existing D-mannose/carbohydrate binding annotations): VIP36 prefers high-mannose Man7-9GlcNAc2 with strongest recognition of the D1/A-arm Man-alpha-1,2-Man-alpha-1,2-Man motif; binding is pH-sensitive (optimum ~pH 6.0-6.5, matching early-Golgi/ERGIC lumen) and structurally Ca2+-assisted (residues Asp131, Asn166, His190 contact ligand). Reinforces the existing core MF; reviews (Gupta 2012, Yamamoto 2014, Reiterer 2010 thesis) are not PubMed-cached primary sources — notes-only, not added to YAML. - Disease/association context (Falcon; non-causal, not gene function): 2024 plasma-proteome PWAS (Xiong et al., Heliyon) associates LMAN2 with CKD-related traits (BUN/eGFR), but colocalization PP4 < 0.01 does NOT support a shared causal cis-variant, so LMAN2 is at best an associated marker; 2023 granulosa-cell proteomics (Eubler et al.) reports LMAN2 as differentially abundant under cannabidiol. Both are association/proteomics only and do not inform VIP36 molecular function; notes-only, not added to YAML.