| Aspect | Evidence-based statement | Key supporting source |
|---|---|---|
| Identity | Human **P3H1** is **LEPRE1/GROS1**, encoding **prolyl 3-hydroxylase 1** (UniProt **Q32P28**), the catalytic component of the ER collagen prolyl 3-hydroxylation machinery that modifies COL1A1 Pro986. (pqac-00000005, pqac-00000004) | Li et al., 2024, **10.1038/s41467-024-52321-6**, https://doi.org/10.1038/s41467-024-52321-6; Chang et al., 2010, **10.1093/hmg/ddp481**, https://doi.org/10.1093/hmg/ddp481 |
| Enzymatic reaction/cofactors | P3H1 is a **2-oxoglutarate/Fe²⁺-dependent dioxygenase** that catalyzes **3-hydroxylation of proline** in collagen, requiring **Fe²⁺, 2-oxoglutarate, O₂, and ascorbate**. (pqac-00000003, pqac-00000005) | Marini et al., 2007, **10.4161/cc.6.14.4474**, https://doi.org/10.4161/cc.6.14.4474; Li et al., 2024, **10.1038/s41467-024-52321-6**, https://doi.org/10.1038/s41467-024-52321-6 |
| Substrate specificity | The best-established substrate is **type I collagen α1(I) Pro986**; loss of P3H1 causes near-complete loss of **3-Hyp986** and collagen overmodification/delayed folding. Additional sites such as **α2(I) Pro707** are modified to a lesser extent. (pqac-00000000, pqac-00000002, pqac-00000007) | Besio et al., 2019, **10.1242/dmm.038521**, https://doi.org/10.1242/dmm.038521; Cabral, 2014; Hudson & Eyre, 2013, **10.3109/03008207.2013.800867**, https://doi.org/10.3109/03008207.2013.800867 |
| Complex partners/stoichiometry | P3H1 forms a stable **P3H1/CRTAP/PPIB (CyPB)** complex in the ER with approximate **1:1:1 stoichiometry**; **CRTAP and P3H1 are mutually stabilizing**, while PPIB provides prolyl cis-trans isomerase activity. (pqac-00000004, pqac-00000005, pqac-00000010) | Chang et al., 2010, **10.1093/hmg/ddp481**, https://doi.org/10.1093/hmg/ddp481; Li et al., 2024, **10.1038/s41467-024-52321-6**, https://doi.org/10.1038/s41467-024-52321-6 |
| Subcellular localization | P3H1 enters the **secretory pathway** via an **N-terminal signal peptide**, contains a **C-terminal ER-retention/retrieval motif (KDEL-like)**, and is experimentally localized to **rough ER/ER-Golgi**; immunostaining is strongest in fibrillar-collagen-rich tissues such as **dermis, tendon, and cartilage**. (pqac-00000020, pqac-00000021, pqac-00000022, pqac-00000023) | Fonsén, 2007; Marini et al., 2007, **10.4161/cc.6.14.4474**, https://doi.org/10.4161/cc.6.14.4474; Cabral, 2014 |
| Key 2024 structural insights | Cryo-EM structures show a **bifunctional reaction center** with **P3H1 and PPIB active sites face-to-face**, multiple collagen-binding sites (**CBS1–5**), and an unexpected **dual-ternary/hetero-hexameric** state whose balance shifts with active-site mutations or **cyclosporin A**. (pqac-00000010, pqac-00000008, pqac-00000028) | Li et al., 2024, **10.1038/s41467-024-52321-6**, https://doi.org/10.1038/s41467-024-52321-6 |
| Disease associations | **Biallelic P3H1/LEPRE1 variants** cause **recessive osteogenesis imperfecta type VIII**, characterized by severe bone fragility, early fractures, collagen overmodification, ER stress, and impaired secretion/folding of type I collagen. (pqac-00000000, pqac-00000004, pqac-00000015) | Besio et al., 2019, **10.1242/dmm.038521**, https://doi.org/10.1242/dmm.038521; Chang et al., 2010, **10.1093/hmg/ddp481**, https://doi.org/10.1093/hmg/ddp481; Cabral, 2014 |
| Quantitative stats | Recent/representative numbers include: PCP complex **~150 kDa**, **~110 Å** long, cryo-EM **~3.17–3.75 Å**; in a 2024 cohort, **3/18** treated rare bone-fragility patients had **P3H1** variants, mean age **9.3 y** (range **5–15**), fracture rate fell from **3.9 to 1.4/year** on bisphosphonates (**p=0.02**); older population data estimate the recurrent West African/African American splice variant carrier frequency at **0.4%** in African Americans and **~1.5%** in some West African cohorts. (pqac-00000010, pqac-00000014, pqac-00000017) | Li et al., 2024, **10.1038/s41467-024-52321-6**, https://doi.org/10.1038/s41467-024-52321-6; Charpié et al., 2024, **10.1038/s41431-024-01645-4**, https://doi.org/10.1038/s41431-024-01645-4; Cabral, 2014 |


*Table: This table summarizes the core functional annotation of human P3H1/LEPRE1 (UniProt Q32P28), including its enzymatic role, substrates, complex partners, localization, 2024 structural advances, disease relevance, and selected quantitative findings. It is useful as a concise evidence map for gene/protein annotation and interpretation.*