ArticleProceedings of the National Academy of Sciences of the United States of America2020
Hidden kinetic traps in multidomain folding highlight the presence of a misfolded but functionally competent intermediate.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 26 citations in OpenAlex.
- Determinants of Protein Folding Pathways: Lessons from Metamorphic Proteins.International journal of molecular sciences · 2026Review
- Dissecting the Structural Features of Folding Asymmetry and Transient Misfolding in a Multidomain PDZ Scaffold.Small science · 2026Article
- Adjacent domains drive the emergence of misfolded intermediates in the folding pathway of the PDZ4 from MAGI1.BBA advances · 2026Article
- A PDZ tandem repeat folds and unfolds via different pathways.Protein science : a publication of the Protein Society · 2024Article
- GRB2: A dynamic adaptor protein orchestrating cellular signaling in health and disease.Biochemistry and biophysics reports · 2024Review
- Folding and Binding Kinetics of the Tandem of SH2 Domains from SHP2.International journal of molecular sciences · 2024Article
- Systematic conformation-to-phenotype mapping via limited deep sequencing of proteins.Molecular cell · 2023Article
- Article
- Cryptic binding properties of a transient folding intermediate in a PDZ tandem repeat.Protein science : a publication of the Protein Society · 2022Article
- On the Effects of Disordered Tails, Supertertiary Structure and Quinary Interactions on the Folding and Function of Protein Domains.Biomolecules · 2022Review
- DNAJB12 and Hsp70 triage arrested intermediates of N1303K-CFTR for endoplasmic reticulum-associated autophagy.Molecular biology of the cell · 2021Article
- Double Mutant Cycles as a Tool to Address Folding, Binding, and Allostery.International journal of molecular sciences · 2021Review
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Authors and funding
10 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Although more than 75% of the proteome is composed of multidomain proteins, current knowledge of protein folding is based primarily on studies of isolated domains. In this work, we describe the folding mechanism of a multidomain tandem construct comprising two distinct covalently bound PDZ domains belonging to a protein called Whirlin, a scaffolding protein of the hearing apparatus. In particular, via a synergy between NMR and kinetic experiments, we demonstrate the presence of a misfolded intermediate that competes with productive folding. In agreement with the view that tandem domain swapping is a potential source of transient misfolding, we demonstrate that such a kinetic trap retains native-like functional activity, as shown by the preserved ability to bind its physiological ligand. Thus, despite the general knowledge that protein misfolding is intimately associated with dysfunction and diseases, we provide a direct example of a functionally competent misfolded state. Remarkably, a bioinformatics analysis of the amino acidic sequence of Whirlin from different species suggests that the tendency to perform tandem domain swapping between PDZ1 and PDZ2 is highly conserved, as demonstrated by their unexpectedly high sequence identity. On the basis of these observations, we discuss on a possible physiological role of such misfolded intermediate.
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