8XWZ

Non-crystalline proximal tubulopathy and crystalline cast nephropathy-causing Bence-Jones protein PT-CN: An entire immunoglobulin kappa light chain dimer

Summary for 8XWZ

• Entry DOI: 10.2210/pdb8xwz/pdb
• Descriptor: Bence-Jones protein kappa light chain PT-CN, PHOSPHATE ION, 2-ETHOXYETHANOL, ... (8 entities in total)
• Functional Keywords: bence-jones protein, immunoglobulin, kappa light chain, immune system
• Biological source: Homo sapiens
• Total number of polymer chains: 2
• Total formula weight: 51902.98

Authors

Ezawa, T.,Otomo, R.,Nozawa, K.,Kyoya, S.,Noguchi, K.,Yohda, M.,Odaka, M.,Matsumura, H. (deposition date: 2024-01-17, release date: 2025-01-22)

Primary citation

Ezawa, T.,Otomo, R.,Kariya, Y.,Nozawa, K.,Kyoya, S.,Furutani, C.,Noguchi, K.,Yohda, M.,Odaka, M.,Matsumura, H.,Saito, A.,Saito, M.,Abe, F.,Fujioka, Y.,Kitadate, A.,Wakui, H.,Takahashi, N.
Multiple myeloma-associated non-crystalline proximal tubulopathy and crystalline cast nephropathy: Biochemical and structural features of disease-causing monoclonal kappa light chains.
Faseb J., 39:e70296-e70296, 2025

PubMed Abstract: Various tubular diseases in patients with multiple myeloma (MM) are caused by monoclonal immunoglobulin light chains (LCs). However, the physicochemical characteristics of the disease-causing LCs contributing to the onset of MM-associated tubular diseases remain unclear. We herein report a rare case of MM-associated combined tubulopathies: non-crystalline light chain proximal tubulopathy (LCPT) and crystalline light chain cast nephropathy (LCCN). The patient's urinary κ-LC (Bence-Jones proteins, BJP-κ PT-CN) was detected through immunofixation. Renal biopsy revealed cytoplasmic vacuoles in swollen proximal tubular cells and distal tubular casts. Immunohistochemistry showed proximal tubular reabsorption granules and distal tubular casts positively stained with an anti-κ-LC antibody. Electron microscopy identified vacuolation and an increased number of lysosomes in proximal tubular epithelial cells without crystalline structures. Distal tubular casts comprised numerous crystals with both rod-shaped and needle-like configurations and tube-shaped materials. To elucidate the molecular mechanisms underlying tubular toxicity, we performed the following physicochemical analyses of BJP-κ PT-CN: N-terminal amino acid sequencing, cDNA cloning, size-exclusion chromatography, thermal shift assays, and X-ray crystallography. The variable segment of BJP-κ PT-CN was derived from the IGKV1-39 gene. The characteristic features of BJP-κ PT-CN were a positively charged surface patch, concentration-dependent monomer-dimer equilibrium, and the R61G mutation. This is the first biochemical and structural characterization of disease-causing BJPs in MM-associated LCPT and crystalline LCCN. The results obtained suggest that these characteristic features enhance protein binding to negatively charged sites on brush-border membranes in proximal tubules and promote the formation of organized casts in distal tubular lumens.

PubMed: 39781602
DOI: 10.1096/fj.202402104R

Experimental method

X-RAY DIFFRACTION (2.3 Å)