Academic Journal
A CDR1 aggregation hotspot controls unfolding kinetics and multimolecular aggregation in IGLV2 light chains.
| Τίτλος: | A CDR1 aggregation hotspot controls unfolding kinetics and multimolecular aggregation in IGLV2 light chains. |
|---|---|
| Συγγραφείς: | Gulyásová T; Department of Biophysics, Faculty of Science, Pavol Jozef Šafárik University, Jesenna 5, Košice 040 01, Slovakia; Center for Interdisciplinary Biosciences, Technology and Innovation Park, Pavol Jozef Šafárik University, Jesenna 5, Košice 040 01, Slovakia., Šipošová K; Department of Biophysics, Institute of Experimental Physics, Slovak Academy of Sciences, Watsonova 47, Košice 040 01, Slovakia., Džupponová V; Center for Interdisciplinary Biosciences, Technology and Innovation Park, Pavol Jozef Šafárik University, Jesenna 5, Košice 040 01, Slovakia. Electronic address: veronika.dzupponova@upjs.sk. |
| Πηγή: | Biochimica et biophysica acta. Proteins and proteomics [Biochim Biophys Acta Proteins Proteom] 2026 Jul 01; Vol. 1874 (4), pp. 141155. Date of Electronic Publication: 2026 May 19. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: Elsevier Country of Publication: Netherlands NLM ID: 101731734 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1878-1454 (Electronic) Linking ISSN: 15709639 NLM ISO Abbreviation: Biochim Biophys Acta Proteins Proteom Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Amsterdam : Elsevier |
| Ιατρικοί όροι (MeSH): | Immunoglobulin Light Chains*/chemistry , Immunoglobulin Light Chains*/genetics , Immunoglobulin Light Chains*/metabolism , Immunoglobulin lambda-Chains*/chemistry , Immunoglobulin lambda-Chains*/genetics , Protein Aggregates*, Recombinant Proteins/chemistry ; Recombinant Proteins/genetics ; Recombinant Proteins/metabolism ; Kinetics ; Protein Unfolding ; Amino Acid Sequence ; Humans ; Calorimetry, Differential Scanning |
| Περίληψη: | Immunoglobulin light chains (LCs) exhibit diverse aggregation behaviours that depend sensitively on sequence composition and intermolecular interactions. Understanding how specific residues modulate aggregation kinetics remains a key challenge in elucidating the molecular basis of light-chain amyloidosis. Here, we investigate sequence-dependent aggregation using recombinant λ LCs derived from the IGLV2 gene family. Comparison of two closely related LCs differing by only 16 amino acids revealed striking differences in aggregation behaviour under thermal stress. Bioinformatic analysis identified an additional aggregation-prone segment in the CDR1 region of the aggregation-prone M10 variant, associated with residues Ser33 and Tyr34. Rational substitution of these residues (S33D/Y34S) markedly reduced aggregation while leaving the thermal transition temperature largely unchanged (∼53 °C). Differential scanning calorimetry revealed that the wild-type M10 LC unfolds with a significantly lower apparent activation energy (∼290 kJ/mol) compared with the non-aggregating H9 (∼605 kJ/mol) and the stabilised double mutant (∼560 kJ/mol), indicating reduced kinetic stability. Aggregation of unfolded species showed much weaker temperature dependence (E (Copyright © 2026 Elsevier B.V. All rights reserved.) |
| Competing Interests: | Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. |
| Substance Nomenclature: | 0 (Immunoglobulin Light Chains) 0 (Protein Aggregates) 0 (Immunoglobulin lambda-Chains) 0 (Recombinant Proteins) |
| Entry Date(s): | Date Created: 20260520 Date Completed: 20260608 Latest Revision: 20260608 |
| Update Code: | 20260608 |
| DOI: | 10.1016/j.bbapap.2026.141155 |
| PMID: | 42162637 |
| Βάση Δεδομένων: | MEDLINE |
καταχωρήστε σχόλιο πρώτοι!