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  organism: human
  gene_id: LMAN2
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  protein_description: 'RecName: Full=Vesicular integral-membrane protein VIP36; AltName:
    Full=Glycoprotein GP36b; AltName: Full=Lectin mannose-binding 2; AltName: Full=Vesicular
    integral-membrane protein 36; Short=VIP36; Flags: Precursor;'
  gene_info: Name=LMAN2; Synonyms=C5orf8;
  organism_full: Homo sapiens (Human).
  protein_family: Not specified in UniProt
  protein_domains: ConA-like_dom_sf. (IPR013320); Intracellular_Lectin-GPT. (IPR051136);
    Lectin_leg. (IPR005052); VIP36_lectin. (IPR035664); Lectin_leg-like (PF03388)
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    \ the VIP36 (LMAN2) cleavage site F298\u2193L299 and its terminomics validation\
    \ are as follows: - *"
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## Question

# Gene Research for Functional Annotation

## ⚠️ CRITICAL: Gene/Protein Identification Context

**BEFORE YOU BEGIN RESEARCH:** You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

### Target Gene/Protein Identity (from UniProt):
- **UniProt Accession:** Q12907
- **Protein Description:** RecName: Full=Vesicular integral-membrane protein VIP36; AltName: Full=Glycoprotein GP36b; AltName: Full=Lectin mannose-binding 2; AltName: Full=Vesicular integral-membrane protein 36; Short=VIP36; Flags: Precursor;
- **Gene Information:** Name=LMAN2; Synonyms=C5orf8;
- **Organism (full):** Homo sapiens (Human).
- **Protein Family:** Not specified in UniProt
- **Key Domains:** ConA-like_dom_sf. (IPR013320); Intracellular_Lectin-GPT. (IPR051136); Lectin_leg. (IPR005052); VIP36_lectin. (IPR035664); Lectin_leg-like (PF03388)

### MANDATORY VERIFICATION STEPS:

1. **Check if the gene symbol "LMAN2" matches the protein description above**
2. **Verify the organism is correct:** Homo sapiens (Human).
3. **Check if protein family/domains align with what you find in literature**
4. **If you find literature for a DIFFERENT gene with the same or similar symbol, STOP**

### If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

**DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE.** Instead:
- State clearly: "The gene symbol 'LMAN2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

### Research Target:

Please provide a comprehensive research report on the gene **LMAN2** (gene ID: LMAN2, UniProt: Q12907) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

## Output

Question: You are an expert researcher providing comprehensive, well-cited information.

Provide detailed information focusing on:
1. Key concepts and definitions with current understanding
2. Recent developments and latest research (prioritize 2023-2024 sources)
3. Current applications and real-world implementations
4. Expert opinions and analysis from authoritative sources
5. Relevant statistics and data from recent studies

Format as a comprehensive research report with proper citations. Include URLs and publication dates where available.
Always prioritize recent, authoritative sources and provide specific citations for all major claims.

# Gene Research for Functional Annotation

## ⚠️ CRITICAL: Gene/Protein Identification Context

**BEFORE YOU BEGIN RESEARCH:** You MUST verify you are researching the CORRECT gene/protein. Gene symbols can be ambiguous, especially for less well-characterized genes from non-model organisms.

### Target Gene/Protein Identity (from UniProt):
- **UniProt Accession:** Q12907
- **Protein Description:** RecName: Full=Vesicular integral-membrane protein VIP36; AltName: Full=Glycoprotein GP36b; AltName: Full=Lectin mannose-binding 2; AltName: Full=Vesicular integral-membrane protein 36; Short=VIP36; Flags: Precursor;
- **Gene Information:** Name=LMAN2; Synonyms=C5orf8;
- **Organism (full):** Homo sapiens (Human).
- **Protein Family:** Not specified in UniProt
- **Key Domains:** ConA-like_dom_sf. (IPR013320); Intracellular_Lectin-GPT. (IPR051136); Lectin_leg. (IPR005052); VIP36_lectin. (IPR035664); Lectin_leg-like (PF03388)

### MANDATORY VERIFICATION STEPS:

1. **Check if the gene symbol "LMAN2" matches the protein description above**
2. **Verify the organism is correct:** Homo sapiens (Human).
3. **Check if protein family/domains align with what you find in literature**
4. **If you find literature for a DIFFERENT gene with the same or similar symbol, STOP**

### If Gene Symbol is Ambiguous or You Cannot Find Relevant Literature:

**DO NOT PROCEED WITH RESEARCH ON A DIFFERENT GENE.** Instead:
- State clearly: "The gene symbol 'LMAN2' is ambiguous or literature is limited for this specific protein"
- Explain what you found (e.g., "Found extensive literature on a different gene with the same symbol in a different organism")
- Describe the protein based ONLY on the UniProt information provided above
- Suggest that the protein function can be inferred from domain/family information

### Research Target:

Please provide a comprehensive research report on the gene **LMAN2** (gene ID: LMAN2, UniProt: Q12907) in human.

The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.

You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.

We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.

We are interested in where in or outside the cell the gene product carries out its function.

We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.

Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.

# Research Report: Human **LMAN2** (VIP36; UniProt **Q12907**) — Functional Annotation

## 1) Identity verification and scope
**Target confirmed:** the UniProt accession **Q12907** corresponds to human **LMAN2**, encoding **Vesicular integral-membrane protein VIP36 (VIP36/GP36b)**, a type I transmembrane **L-type (legume-like) lectin** in the early secretory pathway. This report summarizes experimentally supported function, localization, binding specificity, and recent (2023–2024 prioritized) disease/proteomics associations.

## 2) Key concepts and definitions (current understanding)

### 2.1 L-type (legume-like) lectins in the secretory pathway
LMAN2/VIP36 is part of the **animal L-type lectin** family, defined by a luminal **carbohydrate recognition domain (CRD)** structurally homologous to plant legume lectins and specialized for **high-mannose N-glycan recognition** in luminal secretory compartments. L-type lectins in animals are frequently membrane-anchored and implicated in **protein sorting/trafficking** and **glycoprotein quality control** rather than extracellular lectin functions. (gupta2012ltypelectinsin pages 1-2, yamamoto2014intracellularlectinsare pages 8-10)

### 2.2 Domain architecture and topology
VIP36 is a **type I transmembrane protein** with an N-terminal signal peptide, a luminal lectin CRD, a single-pass transmembrane helix, and a short cytosolic tail. Review-level summaries describe L-type cargo lectins (ERGIC-53/LMAN1 and VIP36/LMAN2) as having: (i) an N-terminal L-type lectin domain, (ii) a proline-rich/stalk region, and (iii) a region near the membrane involved in Ca2+ coordination in family members. (gupta2012ltypelectinsin pages 2-3, veronika2010theroleof pages 22-25)

### 2.3 Subcellular localization and cycling concepts
VIP36 localizes primarily to **Golgi / pre-Golgi (ERGIC)** compartments and exhibits **cycling within the early secretory pathway**. It has been described in **cis/medial Golgi**, **ERGIC**, and transport vesicles; under some contexts it can be detected in **post-Golgi** compartments and at the **plasma membrane** in polarized epithelial cells. This distribution is consistent with a role as a **sorting receptor** that binds luminal glycans in one compartment and releases them in another (e.g., driven by pH differences). (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28)

## 3) Molecular function and mechanism (best-supported functional model)

### 3.1 Primary biochemical activity: high-mannose N-glycan recognition
The primary experimentally supported biochemical function of VIP36 is **binding to high-mannose N-glycans**, particularly glycan determinants enriched early in the secretory pathway.

**Specificity:** VIP36 preferentially recognizes **Man7–Man9GlcNAc2** and shows strong preference for isomers containing the **D1/A-arm Manα1-2–Manα1-2–Man** motif; trimming or masking terminal α1,2-mannose residues abolishes binding in biochemical assays. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11)

**Environmental dependence:** binding is **pH sensitive**, with optimal binding reported around **pH ~6–6.5**, aligning with early Golgi/ERGIC conditions and supporting a compartment-dependent binding/release model. (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11)

**Ca2+ dependence:** structural work indicates VIP36 binds **one Ca2+** adjacent to the carbohydrate-binding site, supporting **Ca2+-dependent ligand coordination**, although some biochemical reports describe partial Ca2+ independence under certain assay conditions, indicating that Ca2+ dependence may be context- and/or method-dependent. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, gupta2012ltypelectinsin pages 12-13)

### 3.2 Structural determinants of glycan binding (experimental residues)
High-resolution structural summaries indicate that Ca2+ positions and/or stabilizes the binding geometry such that **Asp131, Asn166, and His190** form key direct contacts with the ligand, with additional residues (e.g., Gly260, Asp261, Leu262) contributing hydrogen bonds to mannose. These details provide a mechanistic basis for the D1/A-arm preference. (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28)

### 3.3 Cellular role: glycoprotein sorting and “glycan-maturation quality control”
VIP36 is widely framed as an **intracellular cargo receptor/sorting lectin** that recognizes high-mannose glycans and participates in **Golgi/early secretory sorting**. A prominent model is that VIP36 can bind glycoproteins that retain immature high-mannose glycans (e.g., that escaped earlier processing) and help **recycle them for further glycan maturation**, consistent with a **quality-control role in glycosylation state**. (gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 12-13)

## 4) Subcellular localization and trafficking (where function occurs)

### 4.1 Golgi/ERGIC localization and rapid retrograde cycling
VIP36 is described as predominantly Golgi/ERGIC-localized and cycling between compartments of the early secretory pathway. Quantitative FRAP measurements reported in one compiled experimental account indicate approximate half-times of **ER→Golgi t1/2 ~105 ± 39 min** and **Golgi→ER t1/2 ~1.67 ± 0.45 min**, consistent with relatively rapid retrograde movement. (veronika2010theroleof pages 25-28)

### 4.2 Polarized surface distribution (evidence for apical bias)
In polarized epithelial contexts, VIP36 has been reported at the plasma membrane with an **apical/basolateral ratio ~7**, consistent with proposed roles in polarized trafficking/sorting. (gupta2012ltypelectinsin pages 12-13)

### 4.3 Sorting motifs (areas of disagreement)
The cytosolic sorting logic of VIP36 is not as consistently described across sources as for ERGIC-53/LMAN1. One review describes VIP36 as lacking a canonical dilysine ER-localization motif and being mainly Golgi-localized (in contrast to ERGIC-53). (yamamoto2014intracellularlectinsare pages 8-10) In contrast, another compiled account proposes a **C-terminal KRXX** retrieval-like signal and reports rapid retrograde cycling consistent with COPI-mediated retrieval. (veronika2010theroleof pages 25-28) A third source discusses a short C-terminal motif (**KRFY**) associated with cycling in the VIP36/VIPL family, while VIPL has additional determinants for ER retention. (gupta2012ltypelectinsin pages 15-16)

**Interpretation:** overall evidence supports that VIP36 cycles and that its luminal lectin activity is tuned to Golgi/ERGIC conditions; however, the **exact cytosolic motif logic** (KRXX vs other motifs; whether “no dilysine” applies universally) is not fully reconciled within the retrieved evidence and likely depends on isoform/context and/or historical annotation differences. (veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)

## 5) Ectodomain shedding and extracellular detectability

### 5.1 Metalloprotease-sensitive ectodomain cleavage site (direct evidence)
Quantitative protein **terminomics** identified VIP36/LMAN2 as a metalloprotease-regulated shedding substrate with a reproducible cleavage site at **F298↓L299** (reported as **SVNF↓LKSP**) detected across multiple cell lines, and downregulated by the broad-spectrum metalloprotease inhibitor **BB-94**. (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12)

The cropped figure/table evidence documenting the cleavage site and inhibitor-dependent reduction is available here. (tsumagari2021exploringthelandscape media 6d3163dc, tsumagari2021exploringthelandscape media ed8c04ed, tsumagari2021exploringthelandscape media a19a5e2b)

**Implication:** VIP36 can generate a soluble ectodomain fragment under metalloprotease activity, offering a mechanistic basis for detecting VIP36-derived peptides/fragments in extracellular compartments and suggesting regulated remodeling of its lectin function at membranes. (tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12)

## 6) Recent developments (prioritizing 2023–2024)

### 6.1 2024: Plasma proteomics/genetics implicate LMAN2 in kidney traits (candidate biomarker/target)
A 2024 **proteome-wide association study (PWAS)** integrating plasma proteomics (SOMAmer) with GWAS datasets identified **LMAN2** among proteins associated with **chronic kidney disease (CKD)** and replicated signals in related traits (eGFR and BUN). The study used ARIC proteomics with **n=7,213** European-ancestry participants and followed PWAS with Mendelian randomization (MR) and colocalization.

MR results reported: association strongest for **BUN** (OR **1.032**, FDR **5.85×10−3**); MR evidence for CKD was marginal (OR **1.283**, FDR **5.63×10−2**) and not significant for eGFR (OR **0.989**, FDR **0.141**). Colocalization did not support a shared causal cis-variant for LMAN2 with CKD/eGFR/BUN (**PP4 < 0.01**), weakening causal interpretation and indicating that LMAN2 is currently better viewed as an associated marker/candidate pathway component rather than a confirmed causal effector. (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)

**Publication details:** Xiong et al., *Heliyon*, **Jun 2024**. URL: https://doi.org/10.1016/j.heliyon.2024.e31704. (xiong2024plasmaproteomeanalysis pages 1-2)

### 6.2 2023: LMAN2 responds in granulosa-cell proteome under cannabidiol stimulation
In a 2023 study of cultured human granulosa cells treated with **30 µM cannabidiol (CBD) for 24 h** (n=5 biological replicates), LMAN2 (VIP36) was reported as differentially abundant with **log2 fold-change = 1.23** and **q = 0.04**. While this does not define mechanism, it places LMAN2 among regulated proteins under conditions that induced inflammatory/secretory changes in granulosa cells. (eubler2023trpv2anovel pages 9-10)

**Publication details:** Eubler et al., *Molecular Human Reproduction*, **Aug 2023**. URL: https://doi.org/10.1093/molehr/gaad029. (eubler2023trpv2anovel pages 9-10)

### 6.3 Contextual mechanistic synthesis (expert view from authoritative reviews)
Authoritative syntheses emphasize that VIP36’s **pH-dependent** and **high-mannose-specific** recognition is well matched to the chemistry of early Golgi/ERGIC glycan maturation and positions VIP36 as a **glycan-state sensor** that can influence forward trafficking vs retrieval/recycling decisions for glycoproteins. (gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)

## 7) Current applications and real-world implementations

### 7.1 Biomarker discovery and disease association (kidney disease)
Given the PWAS/MR associations, LMAN2 is being discussed as a candidate plasma protein marker linked to CKD-related traits; however, the limited colocalization support indicates caution in interpreting LMAN2 as a drug target without further causal validation. (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)

### 7.2 Potential utility of soluble VIP36 fragments
Because VIP36 undergoes metalloprotease-sensitive ectodomain shedding at a specific site (F298↓L299), assays targeting shed ectodomain fragments could, in principle, serve as **readouts of membrane protease activity and/or secretory-pathway remodeling**, though clinical utility remains to be established. (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape media 6d3163dc)

### 7.3 Clinical trials
A ClinicalTrials.gov-style search performed in this run returned **no clearly relevant interventional clinical trials** targeting LMAN2/VIP36 specifically. (clinical-trials search result context in pqac tool state; no citeable trial context was returned)

## 8) Expert/authoritative pathway-level interpretation

### 8.1 Pathways and processes
The most coherent pathway placement for VIP36 is within **secretory-pathway cargo selection and glycoprotein quality control**, coupling **N-glycan processing state** (high mannose vs processed complex glycans) to **sorting and recycling** in ERGIC/cis-Golgi/TGN trafficking routes. The pH-tuned binding profile (maximal near mildly acidic Golgi conditions) provides a plausible biophysical switch for ligand engagement and release across compartments. (gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)

### 8.2 Distinguishing LMAN2 (VIP36) from related family members
The retrieved reviews emphasize family context with ERGIC-53/LMAN1 and VIPL/LMAN2L, noting that paralogues differ in localization (e.g., VIPL being ER-localized) and sorting signals, reinforcing that **LMAN2/VIP36 is the Golgi/ERGIC cycling lectin** among close homologs. (yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)

## 9) Key statistics and data (compiled)
The following table consolidates quantitative parameters and recent association statistics relevant for functional annotation.

| Finding | Quantitative value(s) | Experimental basis | Source (include DOI URL if available) |
|---|---:|---|---|
| Glycan specificity | Prefers high-mannose **Man7–9GlcNAc2** glycans; strongest recognition of **D1/A-arm Manα1-2Manα1-2Man** motif; trimming or glucosylation of the terminal α1,2-mannose abolishes/reduces binding; one FAC-derived affinity value is reported in review text as **“7.1 × 10^8 M^-1”** for immobilized VIP36 with Man7–9 glycans | Frontal affinity chromatography, competition with Man7–9 glycopeptides, glycan trimming/glucosylation perturbation, and co-crystal structural analysis of the VIP36 CRD | Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Reiterer 2010, https://doi.org/10.5451/unibas-005405317; Yamamoto 2014, https://doi.org/10.2183/pjab.90.67 (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11, gupta2012ltypelectinsin pages 10-12) |
| pH optimum for sugar binding | Optimal binding reported at **~pH 6.5**; other assays reported **~pH 6.0**; binding increases under mildly acidic conditions consistent with Golgi localization | Recombinant CRD binding assays and FAC; review synthesis of primary studies | Reiterer 2010, https://doi.org/10.5451/unibas-005405317; Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Yamamoto 2014, https://doi.org/10.2183/pjab.90.67 (gupta2012ltypelectinsin pages 12-13, veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 10-11) |
| Ca2+ dependence evidence | Structural evidence supports **1 Ca2+** bound adjacent to the carbohydrate-binding site; key residues **Asp131, Asn166, His190** directly contact ligand; however, some biochemical studies reported binding at pH 6.0 without strict Ca2+ dependence, so evidence is mixed | X-ray crystallography of VIP36 CRD with mannosyl ligands plus biochemical glycan-binding assays | Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7; Reiterer 2010, https://doi.org/10.5451/unibas-005405317 (gupta2012ltypelectinsin pages 13-15, veronika2010theroleof pages 25-28, gupta2012ltypelectinsin pages 12-13) |
| Cycling kinetics | **ER→Golgi t1/2 = 105 ± 39 min**; **Golgi→ER t1/2 = 1.67 ± 0.45 min** | FRAP analysis of cycling in the early secretory pathway | Reiterer 2010, https://doi.org/10.5451/unibas-005405317 (veronika2010theroleof pages 25-28) |
| Localization polarity | **Apical/basolateral ratio ≈ 7** in polarized cells | Cell biological localization studies in polarized epithelial cells summarized in review literature | Gupta 2012, https://doi.org/10.1007/978-3-7091-1065-2_7 (gupta2012ltypelectinsin pages 12-13) |
| Ectodomain shedding site | Cleavage at **F298↓L299**; local sequence reported as **SVNF↓LKSP**; detected across all analyzed cell lines and scored as a high-confidence metalloprotease-sensitive shedding site | Quantitative protein terminomics with metalloprotease inhibitor BB-94; cleavage-site mapping and PWM-based sheddase analysis | Tsumagari et al. 2021, https://doi.org/10.1101/2020.09.23.310102 (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12, tsumagari2021exploringthelandscape media 6d3163dc) |
| Recent proteomics association: granulosa cells | **Log2FC = 1.23**, **q = 0.04**, **n = 5** biological replicates | Mass-spectrometry proteomics of cultured human granulosa cells treated 24 h with **30 µM CBD** versus ethanol control | Eubler et al. 2023, https://doi.org/10.1093/molehr/gaad029 (eubler2023trpv2anovel pages 9-10) |
| Recent CKD genetics/proteomics association | PWAS identified LMAN2 among **22** CKD-associated plasma proteins; ARIC proteomics **n = 7,213** European-ancestry participants; MR for **BUN OR = 1.032, FDR = 5.85 × 10^-3**; MR for **CKD OR = 1.283, FDR = 5.63 × 10^-2**; MR for **eGFR OR = 0.989, FDR = 0.141**; colocalization **PP4 < 0.01** for CKD/eGFR/BUN | Proteome-wide association study integrating cis-pQTLs with CKD/eGFR/BUN GWAS, followed by Mendelian randomization and Bayesian colocalization | Xiong et al. 2024, https://doi.org/10.1016/j.heliyon.2024.e31704 (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 9-10, xiong2024plasmaproteomeanalysis pages 7-9) |


*Table: This table compiles the main experimentally supported functional parameters and the most relevant recent quantitative disease/proteomics associations for human LMAN2/VIP36. It is useful as a compact evidence summary for annotation, emphasizing what is measured directly versus what remains inferential or mixed.*

## 10) Complementary genetics/association landscape (Open Targets)
Open Targets lists modest disease-association evidence for LMAN2 across several disease categories (e.g., metabolic syndrome, atopic eczema, allergic disease, respiratory system disease, eye disease), supported by a small set of PubMed-indexed studies (PubMed IDs provided in the Open Targets evidence rows). These associations are **not** mechanistic proofs of VIP36 function in those diseases but can guide hypothesis generation and prioritization. (OpenTargets Search: -LMAN2)

## 11) Limitations and open questions
1. **Mechanistic cargo repertoire in human cells remains incompletely resolved** in the retrieved corpus: while VIP36’s glycan specificity and cycling behavior are well supported, definitive lists of endogenous cargo proteins and direct causal effects on their secretion/processing were not fully available in the accessible texts here. (gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 12-13, yamamoto2014intracellularlectinsare pages 10-11)
2. **Sorting motif logic is inconsistent across summaries**, with some sources emphasizing lack of canonical ER-localization motifs and others proposing KRXX/KRFY-type signals; resolving this likely requires direct sequence/isoform-specific and mutational evidence beyond what was accessible here. (veronika2010theroleof pages 25-28, yamamoto2014intracellularlectinsare pages 8-10, gupta2012ltypelectinsin pages 15-16)
3. **Causality in CKD associations is not established**: MR and colocalization analyses reduce confidence that cis-driven plasma LMAN2 is causally responsible for CKD, despite replicated associations with kidney traits. (xiong2024plasmaproteomeanalysis pages 7-9)

## References (URLs and publication dates)
- Gupta GS. *L-Type Lectins in ER-Golgi Intermediate Compartment*. In: **Animal Lectins: Form, Function and Clinical Applications**. **Mar 2012**. https://doi.org/10.1007/978-3-7091-1065-2_7 (gupta2012ltypelectinsin pages 12-13, gupta2012ltypelectinsin pages 2-3, gupta2012ltypelectinsin pages 13-15)
- Yamamoto K. *Intracellular lectins are involved in quality control of glycoproteins*. **Proceedings of the Japan Academy, Series B**. **Feb 2014**. https://doi.org/10.2183/pjab.90.67 (yamamoto2014intracellularlectinsare pages 8-10, yamamoto2014intracellularlectinsare pages 10-11)
- Suzuki T, Fujihira H. *Folding and Quality Control of Glycoproteins*. In: **Comprehensive Glycoscience**. **Dec 2021**. https://doi.org/10.1016/B978-0-12-409547-2.14947-9 (suzuki2021foldingandquality pages 12-14)
- Tsumagari K, Chang C-H, Ishihama Y. *Exploring the landscape of ectodomain shedding by quantitative protein terminomics*. **iScience** (preprint DOI shown in retrieved text). **Sep 2021**. https://doi.org/10.1101/2020.09.23.310102 (tsumagari2021exploringthelandscape pages 6-8, tsumagari2021exploringthelandscape pages 8-11, tsumagari2021exploringthelandscape pages 11-12, tsumagari2021exploringthelandscape media 6d3163dc)
- Eubler K et al. *TRPV2, a novel player in the human ovary and human granulosa cells*. **Molecular Human Reproduction**. **Aug 2023**. https://doi.org/10.1093/molehr/gaad029 (eubler2023trpv2anovel pages 9-10)
- Xiong Y et al. *Plasma proteome analysis implicates novel proteins as potential therapeutic targets for chronic kidney disease: A proteome-wide association study*. **Heliyon**. **Jun 2024**. https://doi.org/10.1016/j.heliyon.2024.e31704 (xiong2024plasmaproteomeanalysis pages 1-2, xiong2024plasmaproteomeanalysis pages 7-9)


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## Artifacts

- [Edison artifact artifact-00](LMAN2-deep-research-falcon_artifacts/artifact-00.md)
![## Context ID: pqac-00000028 The requested figure and table showing the VIP36 (LMAN2) cleavage site F298↓L299 and its terminomics validation are as follows: - *](LMAN2-deep-research-falcon_artifacts/image-1.png)

## Citations

1. veronika2010theroleof pages 25-28
2. gupta2012ltypelectinsin pages 12-13
3. yamamoto2014intracellularlectinsare pages 8-10
4. gupta2012ltypelectinsin pages 15-16
5. xiong2024plasmaproteomeanalysis pages 1-2
6. xiong2024plasmaproteomeanalysis pages 7-9
7. suzuki2021foldingandquality pages 12-14
8. gupta2012ltypelectinsin pages 1-2
9. gupta2012ltypelectinsin pages 2-3
10. veronika2010theroleof pages 22-25
11. gupta2012ltypelectinsin pages 13-15
12. yamamoto2014intracellularlectinsare pages 10-11
13. tsumagari2021exploringthelandscape pages 6-8
14. tsumagari2021exploringthelandscape pages 8-11
15. tsumagari2021exploringthelandscape pages 11-12
16. gupta2012ltypelectinsin pages 10-12
17. xiong2024plasmaproteomeanalysis pages 9-10
18. https://doi.org/10.1016/j.heliyon.2024.e31704.
19. https://doi.org/10.1093/molehr/gaad029.
20. https://doi.org/10.1007/978-3-7091-1065-2_7;
21. https://doi.org/10.5451/unibas-005405317;
22. https://doi.org/10.2183/pjab.90.67
23. https://doi.org/10.5451/unibas-005405317
24. https://doi.org/10.1007/978-3-7091-1065-2_7
25. https://doi.org/10.1101/2020.09.23.310102
26. https://doi.org/10.1093/molehr/gaad029
27. https://doi.org/10.1016/j.heliyon.2024.e31704
28. https://doi.org/10.1016/B978-0-12-409547-2.14947-9
29. https://doi.org/10.1007/978-3-7091-1065-2\_7,
30. https://doi.org/10.2183/pjab.90.67,
31. https://doi.org/10.5451/unibas-005405317,
32. https://doi.org/10.1101/2020.09.23.310102,
33. https://doi.org/10.1016/j.heliyon.2024.e31704,
34. https://doi.org/10.1093/molehr/gaad029,
35. https://doi.org/10.1016/b978-0-12-409547-2.14947-9,